Volume 1 - Number 1 May - September 1997
Volume 24 - Number 1 January 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.
It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.
See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf
Editorial correspondance
Jean-Loup Huret, MD, PhD, [email protected]
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The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).
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The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Editors-in-Chief Jesús María Hernández Rivas (Salamanca, Spain) Paola Dal Cin (Boston, Massachusetts) Jean-Loup Huret (Poitiers, France) Hematology Section Editor Ana E. Rodríguez, Teresa Gonzalez (Salamanca, Spain) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editor Cécile Badoual (Paris, France) Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts) Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland) Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy) Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil) DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands) Epigenetics Section Editor Roberto Piergentili (Rome, Italy) Hematopoeisis Section Editor Olga Weinberg (Boston, Massachusetts) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren, Barnabas Nyesiga (Malmö, Sweden)
Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Department of Health Sciences, University of Milan, Italy; [email protected] Beghini Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; Antonio Cuneo [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, François Desangles 91223 Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Kessel Nijmegen, The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Oskar A. Haas Research Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Roderick Mc Leod Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected]
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; Roberta Vanni [email protected]
Volume 24, Number 1, January 2020
Table of contents
Gene Section
CRLF2 (Cytokine receptor like factor 2) 1 Dafné Moreno-Lorenzana, RocÍo Juárez-Velázquez, Daniel Martínez-Anaya, Patricia Péez-Vera PHLDA3 (Pleckstrin Homology-Like Domain, family A, member 3) 8 Mércia P Ferreira and Maria A. Nagai SREBF1 (sterol regulatory element binding transcription factor 1) 13 Seher Gök FANCB (FA complementation group B) 18 Sylvie van Twest, Andrew Deans AQP1 (aquaporin 1 (Colton blood group)) 22 Jean Loup Huret AQP2 (aquaporin 2) 28 Jean Loup Huret BUB3 (BUB3 mitotic checkpoint protein) 33 Jorge Antonio Elias Godoy Carlos, João Agostinho Machado-Neto SLC6A4 (solute carrier family 6 member 4) 39 Rafig Gurbanov, Berkay Kalkanci
Leukaemia Section t(6;12)(q22;p13) ETV6/FRK 51 Tatiana Gindina
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CRLF2 (Cytokine receptor like factor 2) Dafné Moreno-Lorenzana, RocÍo Juárez-Velázquez, Daniel Martínez-Anaya, Patricia Péez- Vera Laboratorio de Genética y Cáncer. Instituto Nacional de Pediatría (DML, RJV, DMA, PPV); Cátedra CONACYT-Instituto Nacional de Pediatría (DML); Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México (DMA). / e-Mail [email protected]
Published in Atlas Database: February 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/CRLF2ID51262chXp22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70641/02-2019-CRLF2ID51262chXp22.pdf DOI: 10.4267/2042/70641 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Identity CRLF2 is a member of type I cytokine receptor Other names: CRL2, TSLPR family. CRLF2 forms a functional complex with IL- HGNC (Hugo): CRLF2 7 receptor α chain and thymic stromal Location: Xp22.33 and Yp11.2, negative strand. lymphopoietin, this complex induces the activation ENSG00000205755 of signal transducers and activators of transcription proteins. The overexpression of CRLF2 induced by Local order genetic rearrangements has been described in acute CRLF2 is located on chromosome X and Y, on the lymphoblastic leukemia. short arm and lies between RPL14P5 (ribosomal Keywords protein L4 pseudogene 5) and CSF2RA (colony stimulating factor 2 receptor alpha subunit). Entrez CRLF2; Cytokine receptor; TSLP; Jak-Stat pathway. Gene ID: 64109
Figure 1. A) Chromosomal location of CRLF2 gene. B) Mapping of CRLF2 gene and local order on genomic context of the chromosome X and Y.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 1 CRLF2 (Cytokine receptor like factor 2) Moreno-Lorenzana D et al.
Figure 2. Chromosomes obtained from MHH-CALL-4 cell line positive to IGH/CRLF2 translocation detected by fluorescence in situ hybridization (FISH). The der(Y) chromosome is lost in the cell line. Metaphase hybridized with CRLF2 break-apart probe (Cytocell Aquarius) with a normal chromosome X (green-red signal, yellow arrow), and der(14) (green signal, white arrow).
Figure 3. CRLF2 gene encodes four transcript variants: two with 8 exons, one with 9 exons, and one with 7 exons (exons are represented by violet boxes and introns by black line). ENSG00000205755, Entrez Gene ID: 64109
lung > bladder > small intestine > esophagus > DNA/RNA stomach > skin > prostate > uterus > vagina > testes Description > colon > spleen > mammary gland > thyroid > whole blood. CRLF2 gene is located in reverse strand of pseudo- It has been reported that in pathological conditions autosomal region 1 (PAR1) in X and Y the transcription rate of CRLF2 is altered. CRLF2 chromosomes. CRLF2 encompasses 22kb of DNA overexpression (fold change > 2) is found in: and give rise to four transcript variants with different microbial infection, immunodeficiency syndromes lengths: 1.6, 1.5, 1.0 and 1.7 kb. ENSG00000205755 (X-linked hyper IgM syndrome), autoimmune Transcription diseases (arthritis), and cancer (esophagus dysplasia, CRLF2 gene encodes a member of type I cytokine papillary thyroid carcinoma and acute lymphoblastic receptor family and generate four transcript variants leukemia). The CRLF2 subexpression (fold change (Table 1). Three generate protein coding transcripts < 2) has been reported only in cancer and one generates a non-sense mediated decay (myelodysplastic syndrome, non-small cell lung transcript. carcinoma, hepatobiliary carcinoma, colorectal According with gene expression array data CRLF2 carcinoma, pancreatic adenocarcinoma and breast is expressed, from highest to lowest, in: cervix > carcinoma). ENSG00000205755; UniProt Q9HC73; neXtProt NX_Q9HC73 Table 1. Transcript variants and proteins Name (RefSeq) Exons Coding Exons Transcript Length Protein Length Type of transcript CRLF2-203 (NM_022148) 8 8 1, 639 bp 371 residues Protein coding CRLF2-201 9 8 1, 545 bp 371 residues Protein coding CRLF2-202 (NM_001012288) 7 6 1, 013 bp 259 residues Protein coding CRLF2-204 (NR_110830) 8 5 1, 789 bp 232 residues Non-sense mediated decay
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 2
CRLF2 (Cytokine receptor like factor 2) Moreno-Lorenzana D et al.
Figure 4. Isoform 1 is a single-pass type I membrane protein, have a length of 371 aa. Protein sequence includes four main regions: FN3 (Fibronectin type 3), encompassed from 109 to 207 aa; WSXWS motif, encompassed from 200 to 204 aa; Box 1 motif encompassed from 261 to 269 aa; Transmembrane region encompassed from 232 to 252 aa. Isoform 2 is a secreted protein an only have FN3 region, encompassed from 7 to 76 aa.
(IL-7 receptor α chain) and TSLP (thymic stromal Protein lymphopoietin). Functional complex activation induces different Description signals depending on the type of cell and also exerts CRLF2 gene encodes a member of the type I multiple functions. Heterocomplex is involved in a cytokine receptor family. CRLF2 has three protein plethora of physiologic and pathologic immune coding transcripts: CRLF2-201, CRLF2-202, functions, including: tolerance, allergy, autoimmune CRLF2-203 and CRLF2-204. diseases and cancer. (Tsilingin et al., 2017). CRLF2-203 and CRLF2-201 transcript variants CRLF2 is expressed mainly in dendritic cells and generate the longer isoform of 371 amino acids (42 also hematopoietic cells including T cells, B cells, kDa), also called isoform 1. granulocytes, and mast cells. Isoform 1 has the protein regions that characterize Heterocomplex main function is the differentiation this family gene: FN3 (Fibronectin type 3) region, to T helper type 2 (Th2) cells. CRLF2-activated WSXWS motif, Box 1 motif, and transmembrane dendritic cells express OX40 ligand and trigger region. Post-translational modifications of CRLF2 naive CD4+ to differentiate into inflammatory Th2 protein include glycosylation at asparagine residues cells and the expansion of allergen-specific Th2 (Asn169, Asn55 and Asn47) and phosphorylation at memory cells (Lin et al., 2018). isoleucine (Ile271) and tyrosine (Tyr74) residues. According with phosphoproteome analysis in The other isoform, called isoform 2, is encoded by diverse cell types, after TSLP binds to the the transcript variant CRLF2-202. This isoform is CRLF2/IL-7Rα heterocomplex, the phosphorylation shorter, 259 amino acids (26.6 kDa), at N-terminus of Janus kinase1 (JAK1) and 2 (JAK2) activates compared with isoform 1 because lacks an alternate signal transducers and activators of transcription exon which results in translation initiation at a (STATs) proteins, including: STAT1, STAT3, downstream start codon. ENSG00000205755; STAT4, STAT5A, STAT5B and STAT6. UniProt Q9HC73, Q9HC73-2, Q4V300; neXtProt Heterocomplex also activates other signaling NX_Q9HC73 molecules such as PI3K/AKT/MTOR pathway, SRC Expression / TEC pathway, MAPK3 / MAPK1 (ERK1/2), NF- kB, MAPK8 / MAPK9 (JNK1 JNK2), and CRLF2 protein is present in intestine, bone marrow, p38/MAPK activation (Zhong Jun et al., 2012; spleen, thymus, and is more abundant in dendritic Zhong Jun et al., 2014). cells. neXtProt NX_Q9HC73 In allergy or autoimmune disease has been described Localisation high expression of TSLP and overstimulation of CRLF2 isoform 1 is a cell membrane protein and TSLP/CRLF2/IL-7Rα complex. Tezepelumab is a CRLF2 isoform 2 is a secreted protein. human monoclonal antibody that blocks functional complex and is successfully used in asthma Function treatment (Van Rompaey et al., 2012). CRLF2 forms a functional complex with IL-7Rα
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 3
CRLF2 (Cytokine receptor like factor 2) Moreno-Lorenzana D et al.
Figure 5. A) TSLP /CRLF2/ IL7R complex activation is implicated in Th2 differentiation. TSLP binds to CRLF2/IL-7Rα heterodimer in dendritic cells and promotes the expression of OX40 ligand ( TNFSF4 (CD252)) and IL13, IL5, IL4 and TNF to induce Th2 differentiation. B) TSLP/CRLF2/IL-7Rα complex activation in dendritic cells. Activation of CRLF2 was described by first time in dendritic cells. This scheme exemplifies the main nodes involved.
The role of functional heterocomplex in cancer is been associated with better prognostic. In addition still controversial, in certain neoplasia plays a pro- to above, CRLF2 gene has genetic alterations that tumorigenic role, whereas in others, a protective promote cell survival in cancer. role. The genetic rearrangements P2RY8/CRLF2 and For example, in cervix, breast, and pancreas cancer IGH/CRLF2, generate CRLF2 overexpression, and has been describe an increase of metastasis the mutation Phe232Cys, encodes CRLF2 proteins associated with an overstimulation of capable of forming homodimers and self-activation, TSLP/CRLF2/IL-7Rα. On the other hand, in colon both described in acute lymphoblastic leukemia and skin carcinoma, functional heterocomplex has (Varricchi et al., 2018; Zhong Jun, 2014).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 4
CRLF2 (Cytokine receptor like factor 2) Moreno-Lorenzana D et al.
Figure 6. C) Phosphoproteomic analysis reveals multiple targets in TSLP/CRLF2/IL-7Rα pathway in different cell types. This scheme shows experimental curated data obtained from NetSlim. Homology
Table 2. CRLF2 Orthologues Name Organism CRLF2 P. troglodytes CRLF2 (ENSCAFG00000011034) C. lupus LOC529792 (ENSBTAG00000020242) B. taurus Crlf2 (ENSMUSG00000033467) M. musculus Crlf2 (ENSRNOG00000049828) R. novergicus LOC418668 (ENSGALG00000016696) G. gallus Mutations
See Figure 7. Figure 7. Mutations in CRLF2 have been identified in a wide range of cancer types. Most of them are missense mutations (green), nonsense mutations are also represented (violet).Somatic
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 5
CRLF2 (Cytokine receptor like factor 2) Moreno-Lorenzana D et al.
Type of c.734C>T Breast Carcinoma Missense CDS Mutation Cancer Type Mutation c.526G>C Breast Carcinoma Missense c.315C>A Bladder Carcinoma Missense c.297C>G Cervix Carcinoma Missense c.357C>A Bladder Carcinoma Missense c.658G>C Cervix Carcinoma Missense c.193G>A Bladder Carcinoma Missense Endometrium c.566C>T Missense c.89T>A Bladder Carcinoma Missense Carcinoma Diffuse Large B Endometrium c.33C>G Missense c.536A>T Missense Cell Lymphoma Carcinoma Diffuse Large B Endometrium c.415T>C Missense c.643C>T Missense Cell Lymphoma Carcinoma Endometrium c.349C>T Osteosarcoma Missense c.7C>T Missense Carcinoma c.330T>C Colon Carcinoma Missense Endometrium c.496A>C Missense c.384G>A Colon Carcinoma Missense Carcinoma c.33C>G Colon Carcinoma Missense Endometrium c.373G>A Missense c.159G>A Rectum Carcinoma Missense Carcinoma c.474C>T Adenocarcinoma Missense Endometrium c.346T>C Missense Carcinoma c.372C>T Adenocarcinoma Missense Endometrium c.411G>A Adenocarcinoma Missense c.495A>C Missense Carcinoma c.603C>T Adenocarcinoma Missense c.248G>T Kidney Carcinoma Missense c.405G>A Adenocarcinoma Missense c.526G>A Liver Carcinoma Missense c.669G>A Adenocarcinoma Missense c.105C>G Liver Carcinoma Missense c.642T>C Adenocarcinoma Missense Acute Myeloid c.671C>T Missense Endometrioid Leukemia c.642T>C Missense Carcinoma B Cell Acute c.321C>T Lung Carcinoma Missense c.695T>G Lymphoblastic Missense Leukemia c.384G>A Pleura Carcinoma Missense Mantle Cell c.456C>T Melanoma Missense c.2T>A Missense Lymphoma c.411G>A Melanoma Missense Marginal Zone c.340G>C Missense c.468C>T Melanoma Missense Lymphoma c.123C>T Melanoma Missense Head and Neck c.228C>T Missense Carcinoma c.630G>A Melanoma Missense c.764G>A Melanoma No sense c.534G>A Melanoma Missense c.764G>A Melanoma No sense c.438C>T Melanoma Missense Head and Neck Merkel Cell c.755G>A No sense c.383C>T Missense Carcinoma Carcinoma c.755G>A Melanoma No sense Merkel Cell c-.335G>T Missense Carcinoma c.451C>T Melanoma No sense Urinary Tract c.628C>T Pancreas No sense c.604G>A Missense Carcinoma c.137G>A Colon Carcinoma No sense Urinary Tract c.742C>A Missense Intestinal Carcinoma c.620C>G No sense Adenocarcinoma c.208C>A Neuroblastoma Missense Glioblastoma c.91C>T No sense c.139A>T Glioma Missense Multiforme c.404C>T Glioma Missense c.73G>T Adenocarcinoma No sense c.365C>T Glioma Missense Head and Neck c.54G>A No sense Carcinoma c.598C>A Glioma Missense c.25G>T Lung Carcinoma No sense c.404C>T Glioma Missense c.313C>T Glioma Missense Table 3 CRLF2 mutations in cancer c.74G>A Glioma Missense Catalogue of Somatic Mutations in Cancer; cBioPortal for c.632G>A Glioma Missense Cancer Genomics c.445G>A Meningioma Missense c.660G>T Breast Carcinoma Missense
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 6 CRLF2 (Cytokine receptor like factor 2) Moreno-Lorenzana D et al.
Implicated in References Hematological malignancies Chiu CY, Su SC, Fan WL, Lai SH, Tsai MH, Chen SH, Wong KS, Chung WH. Whole-Genome Sequencing of a Family Oncogenesis with Hereditary Pulmonary Alveolar Proteinosis Identifies a The t(X;14)(p22;q32) or t(Y;14)(p11;q32) rearrange Rare Structural Variant Involving CSF2RA/CRLF2/IL3RA Gene Disruption. Sci Rep. 2017 Feb 24;7:43469 CRLF2 with immunoglobulin heavy chain gene forming IGH/CRLF2 rearrangement. With P2Y Lin SC, Cheng FY, Liu JJ, Ye YL. Expression and purinoceptor 8 gene ( P2RY8), located also in the Regulation of Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin Receptor Heterocomplex in the pseudoautosomal (PAR1) region of X or Y Innate-Adaptive Immunity of Pediatric Asthma. Int J Mol Sci. chromosomes, CRLF2 forms a rearrangement 2018 Apr 18;19(4) through the interstitial deletions del(X)(p22p22) or Nieländer I, Martín-Subero JI, Wagner F, Baudis M, Gesk del(Y)(p11p11). Both abnormalities are associated S, Harder L, Hasenclever D, Klapper W, Kreuz M, Pott C, with B-precursor acute lymphoblastic leukemia (pre- Martinez-Climent JA, Dreyling M, Arnold N, Siebert R. B ALL) and Down syndrome pre-B ALL (Entrez Recurrent loss of the Y chromosome and homozygous deletions within the pseudoautosomal region 1: association Gene ID: 64109; Russell LJ et al., 2009). with male predominance in mantle cell lymphoma. It has been referred similar deletions in the PAR1 Haematologica. 2008 Jun;93(6):949-50 region involving the interleukin 3 receptor subunit Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, alpha ( IL3RA) gene or the colony stimulating factor Calasanz MJ, Chandrasekaran T, Chapiro E, Gesk S, 2 receptor alpha subunit (CSF2RA) gene and Griffiths M, Guttery DS, Haferlach C, Harder L, Heidenreich CRLF2, indicating that the breakpoints are variable O, Irving J, Kearney L, Nguyen-Khac F, Machado L, Minto between patients. Interestingly, one patient has been L, Majid A, Moorman AV, Morrison H, Rand V, Strefford JC, Schwab C, Tönnies H, Dyer MJ, Siebert R, Harrison CJ. reported with the CSF2RA/CRLF2 rearrangement Deregulated expression of cytokine receptor gene, CRLF2, and IGH/ EPOR (Yano M et al., 2015). These is involved in lymphoid transformation in B-cell precursor rearrangements produce the overexpression of acute lymphoblastic leukemia. Blood. 2009 Sep CRLF2 by the juxtaposition of this gene within the 24;114(13):2688-98 gene promoter of P2RY8, AKAP17A (SFRS17A), Tsilingiri K, Fornasa G, Rescigno M. Thymic Stromal or ASMT (Russell LJ et al., 2009). Biallelic Lymphopoietin: to cut a long story short Cell Mol deletions of the PAR1 region, including CSF2RA Gastroenterol Hepatol. 2017; 3(2):174-182 and CRLF2 genes, have been reported in mantle cell Van Rompaey D, Verstraete K, Peelman F, Savvides SN, lymphoma (Nieländer I et al., 2008). Augustyns K, Van Der Veken P, De Winter H. Virtual screening for inhibitors of the human TSLP: TSLPR In addition, four fusions with CRLF2 have been also interaction Sci Rep. 2017; 1: 17211 reported: 1) CHRFAM7A /CRLF2 with the cholinergic receptor, nicotinic, alpha 7, exons 5-10 Varricchi G, Pecoraro A, Marone G, Criscuolo G, Spadaro G, Genovese A, Marone G. Thymic stromal lymphopoietin and he family with sequence similarity 7A, exons A- isoforms, inflammatory disorders and cancer Front E fusion gene (CHRNA7) located in 15q13 (Fusion Immunol. 2018; 9: 1595 gen ID: 7161); 2) CRLF2/ U2AF1 with the U2 small Yano M, Imamura T, Asai D, Kiyokawa N, Nakabayashi K, nuclear RNA auxiliary factor 1 gene (U2F1), Matsumoto K, Deguchi T, Hashii Y, Honda YK, Hasegawa associated with myelodysplastic syndrome, and D, Sasahara Y, Ishii M, Kosaka Y, Kato K, Shima M, Hori H, located in 21q22.3 (Fusion gen ID: 8499); 3) Yumura-Yagi K, Hara J, Oda M, Horibe K, Ichikawa H, Sato A. Identification of novel kinase fusion transcripts in GOLGA8A /CRLF2 with the golgin A8 family paediatric B cell precursor acute lymphoblastic leukaemia member A gene (GOLGA8A) in 15q14 (Fusion gen with IKZF1 deletion Br J Haematol. 2015;171(5):813-7 ID: 15056); 4) WDR27 /CRLF2 with the WD repeat Zhong J, Kim MS, Chaerkady R, Wu X, Huang TC, Getnet domain 27 gene (WDR27) in 6q27 (Fusion gen ID: D, Mitchell CJ, Palapetta SM, Sharma J, O'Meally RN, Cole 41824). RN, Yoda A, Moritz A, Loriaux MM, Rush J, Weinstock DM, Tyner JW, Pandey A. TSLP signaling network revealed by Pulmonary alveolar proteinosis SILAC-based phosphoproteomics Mol Cell Proteomics. A recessive pattern of another similar homozygous 2012;11(6):M112.017764 deletion, that disrupts CSF2RA, CRLF2, and IL3RA Zhong J, Sharma J, Raju R, Palapetta SM, Prasad TS, gene, was found in a boy with pulmonary alveolar Huang TC, Yoda A, Tyner JW, van Bodegom D, Weinstock proteinosis, an accumulation of surfactant in the DM, Ziegler SF, Pandey A. TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling Database alveoli. Surfactant is cleared by alveolar (Oxford).2014:bau007. macrophages, and granulocyte-macrophage colony- stimulating factor (GM-CSF) and its signaling is This article should be referenced as such: necessary for this process. GM-CSF activates Jak- Moreno-Lorenzana D ,2, Juárez-Velázquez R, MartÍnez- Stat pathway inducing phagocytic functions of Anaya D,3, Péez Vera P. CRLF2 (Cytokine receptor like alveolar macrophage and catabolize surfactant (Chiu factor 2). Atlas Genet Cytogenet Oncol Haematol. 2020; CY et al., 2017). 24(1):1-7.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 7 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Review
PHLDA3 (Pleckstrin Homology-Like Domain, family A, member 3) Mércia P Ferreira and Maria A. Nagai Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of Sâo Paulo, 01246-903 and Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of the State of Sâo Paulo (ICESP), 01246-000, Sâo Paulo, Brazil; [email protected]
Published in Atlas Database: February 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/PHLDA3ID50708ch1q32.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70642/02-2019-PHLDA3ID50708ch1q32.pdf DOI: 10.4267/2042/70642 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
and Ohki, 2017; Christgen et al., 2012; Leszczynska Abstract et al., 2015). The DNA of PHLDA3 contains 3 exons and encodes a 2.74 kb mRNA with Review on PHLDA3, with data on DNA, on the a coding region of 383bp. protein encoded, and where the gene is implicated. Keywords DNA/RNA PHLDA3; Tumor suppressor; Apoptosis; Hypoxia Description Identity DNA size: 4,888 kb; 3 exons Other names: TIH1 Transcription HGNC (Hugo): PHLDA3 mRNA size: 2734bp NM_012396.4. Three Location: 1q32.1 transcript variants encoding different isoforms and three non-coding transcripts variants have been Location (base pair) descript for this gene. Starts at 201464284 and ends at 201469171 bp from NM_012396 - Homo sapiens pleckstrin homology- pter (GRCh38.p12 - 21/12/2017) like domain, family A, member 3 (PHLDA3), Note transcript variant 1, mRNA-> NP_036528. PHLDA3 was mapped to human chromosome Transcript size: 2734bp. Translation length: 127 1q32.1 and consist of 4,888 base pairs, starting at residues. base pair 201464284 and ending at base pair https://www.ncbi.nlm.nih.gov/nuccore/NM_012396 201469171 from the p-terminus, it is a TP53 .4 - 28 May, 2015. Variant 1 encodes the functional responsive gene and is required for TP53-dependent protein. apoptosis (Frank et al., 1999; Kawase et al., 2009). NR_073080 - Homo sapiens pleckstrin homology This gene is a member of the Pleckstrin Homology- like domain family A member 3 (PHLDA3), Like Domain A family, which includes PHLDA1, transcript variant 2, non-coding RNA. Transcript PHLDA2, and PHLDA3. PHLDA3 downregulation size: 1625 bp. has been correlated with DNA hypermethylation in https://www.ncbi.nlm.nih.gov/nuccore/NR_073080. some types of cancer as prostate (Mahapatra et al., 1 - 23 - Dec - 2018 2012) and neuroendocrine tumors, and also with ENST00000367311.4 - Homo sapiens pleckstrin TP53 mutation in neuroendocrine tumors and homology like domain family A member 3 mammary carcinomas (Ohki et al., 2014; Takikawa (PHLDA3), transcript variant, protein coding,
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 8 PHLDA3 (Pleckstrin Homology-Like Domain, family A, Ferreira MP, Nagai MA member 3)
mRNA -> NP_036528, NM_012396. Transcript phosphate (PIP): (PI(3)P, PI(4)P, PI(5)P, PI(3,4)P2, size: 2640 bp Translation length: 127 residues. PI(4,5)P2, PI(3,5)P2 and PI(3,4,5)P3) (Kawase et http://www.ensembl.org/id/ENST00000367311.4 al., 2009; Saxena et al., 2002). PHLDA3 has been ENST00000367309.1 - Homo sapiens pleckstrin reported as an AKT1 (Akt) pathway inhibitor and homology like domain family A member 3 associated with tumor suppression (Kawase et al., (PHLDA3), transcript variant, protein coding. 2009). Transcript size: 896 bp. Translation length: 127 residues. Expression http://www.ensembl.org/id/ENST00000367309.1 A RNA-seq performed in different tissue samples ENST00000485436.1 - Homo sapiens pleckstrin shown that PHLDA3 is broadly expressed in adrenal, homology like domain family A member 3 appendix, brain, colon, duodenum, endometrium, (PHLDA3), transcript variant, non-coding RNA. esophagus, fat, gall bladder, heart, kidney, liver, Transcript size: 661 bp. lung, lymph node, ovary, pancreas, placenta, http://www.ensembl.org/id/ENST00000485436.1 prostate, salivary gland, skin, small intestine, spleen, ENST00000497057.1 - Homo sapiens pleckstrin stomach, testis, thyroid and urinary bladder tissue homology like domain family A member 3 (Fagerberg et al., 2014). PHLDA3 expression has (PHLDA3), transcript variant, non-coding RNA. been shown to be modulated by promoter Transcript size: 582 bp. methylation in prostate cancer and TP53 mutations http://www.ensembl.org/id/ENST00000497057.1 in human infiltrating lobular breast cancer cells (Christgen et al., 2012; Mahapatra et al., 2012). Also, Protein besides TP53 it was described that XBP1 transcription factor is implicated in PHLDA3 NP_036528.1. Molecular weight: 13.9 kDa, 127 aa. induction upon ER stress (Han et al., 2016). https://www.ncbi.nlm.nih.gov/protein/NP_036528. PHLDA3 was identified as a gene modulated by 1 - 23/Dec/18 ochratoxin A (OTA) induced genotoxicity, it was upregulated in renal outer medulla cells after treatment with the renal carcinogen OTA in response to DNA damage. In other toxicogenomics studies, Figure 1. Schematic representation of the PHLDA3 PHLDA3 was also proposed as a potential biomarker protein structure. The structure of the PHLDA3 protein is (Ellinger-Ziegelbauer et al., 2008; Furihata et al., composed mainly of the pleckstrin like-domain (PHL). 2018; Hibi et al., 2013; Uehara et al., 2008). Description Localisation PHLDA3 is a 13.9kDa protein, composed of 127 amino mostly comprised of the PHL domain (120aa) PHLDA3 is primarly localized at the plasmatic (Frank et al., 1999). PHLDA3 PHL domain confers membrane due its specificity binding to membrane to this protein the ability of binding specifically to phosphoinositides but can also be find in the membrane lipids. According to in vitro binding cytoplasm and extracellular content. assay, PHLDA3 protein binds to a wide combination of phosphatidylinositol
Figure 2 - Schematic diagram of the modulators and biological effects of PHDA3 expression. PHLDA3 is a p53-target gene activated in response to DNA damage and hypoxia. The gene can also be activated by Xbp1 in response to endoplasmic reticulum stress (ER stress). PHLDA3 induction leads to Akt pathway inhibition by binding to phosphoinositide competition leading to increased apoptosis and proliferation, and decreased cell reprograming efficiency.
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PHLDA3 (Pleckstrin Homology-Like Domain, family A, Ferreira MP, Nagai MA member 3)
Function expression in microglia, the resident macrophage in the CNS, data provide insights into the participation Murine PHLDA3 was first identified in 1999 and of PHLDA3 in the activation status of microglia was designated Tih1 as the closest paralog of the under pathological conditions (Koso et al., 2016). imprinted gene Ipl (Frank et al., 1999). It was PHLDA3 was the most significantly affected gene reported as a tumor suppressor gene. PHLDA3 by thrombin knockout in zebrafish embryos but protein function is still being studied, but it was PHLDA3 function in embryonic development is still reported as an AKT1 (Akt) pathway repressor by unclear (Day and Jagadeeswaran, 2009). preventing Akt-binding to membrane lipids. Thus, The process of endomitosis consists of several PHLDA3 is a TP53 regulated repressor of Akt rounds of DNA synthesis without division and signaling by binding competition, so inhibits Akt leading to polyploidization in megakaryocytes. activity via competitive binding to PIP3 (Kawase et Downregulation of TP53-target genes in TP53 al., 2009) and thereby acts as a dominant-negative knock-down megakaryocytes supports the form of Akt contributing to TP53-dependent hypothesis that TP53 suppresses polyploidization apoptosis. It was reported that active TP53 localizes during megakaryocytic differentiation by arresting to the transcription start site of PHLDA3 and DNA synthesis and inducing apoptosis. PHLDA3 transcriptionally activates this gene. PHLDA3 was together with other genes was identified as a gene upregulated by hypoxia (Leszczynska et al., 2015), through which TP53 mediates these biological and there is a clear accumulation of TP53 at the effects in megakaryocytes (Apostolidis et al., 2012). response elements identified in PHLDA3, demonstrating direct transactivation of these genes Homology in response to hypoxia in colorectal carcinoma, non- PHLDA3 gene is highly conserved in Euteleostomi small-cell lung carcinoma, and nontumor lung and homologs have been found in P.troglodytes, fibroblast cells. It was observed after cisplatin M.mulatta, M.musculus, R.norvegicus, G.gallus and treatment in testicular germ cell-derived human D.rerio. embryonal carcinoma cells that PHLDA3 and other genes downstream targets of TP53 are involved in Implicated in response to DNA damage and events leading to cell death (Kerley-Hamilton et al., 2005). Tumor suppressor In renal tubular cells, cisplatin increases PHLDA3 in PHLDA3 represses Akt activity and Akt-regulated kidneys' tubules and in urinary content suggesting biological processes including insulin-mediated PHLDA3 protein as a kidney injury marker since it glucose transport, protein and glycogen synthesis, is urine-detectable (Lee et al., 2014; Lee, Kang, and proliferation, cell growth, differentiation, and Kim 2015). survival. Pancancer genomics analyses of human Furthermore, PHLDA3 exhibited statistically cancer shown that TP53 mutation is significantly significant changes in gene expression in liver related to PHLDA3, TNFRSF10B and PTEN samples of rats treated with genotoxic downregulation. Thus, a TP53 mutation may cause hepatocarcinogens, suggesting that it may be a tumor development due to the loss of basal TP53 candidate marker gene for differentiating genotoxic target expression together with the TP53 mutant hepatocarcinogens from non-genotoxic inability to active stress-responsive genes as hepatocarcinogens (Suenaga et al., 2013). There is PHLDA3 (Pappas et al., 2017). PHLDA3 suppresses evidence that PHLDA3 is involved in zebrafish neuroendocrine tumorigenicity and deficiency of embryogenesis since PHLDA3 overexpression this gene results in islet resistance to oxidative stress disrupted hemangioblast specification and affected leading to increased proliferation, cell death intersegmental vessel development (ISV). It was prevention and improved insulin-releasing function suggested that overexpression of PHLDA3 inhibits without causing tumors. It was also observed in ISV development by blocking the activation of AKT, PHLDA3-deficient islet enhanced activation of Akt it is supported by data showing a reversal of ISV in response to hypoxia, thereby inducing signaling defects induced by phlda3 overexpression upon Akt pathways of apoptosis inhibition, and cellular constitutively active form expression (Wang et al., growth and survival (Sakata et al., 2017). It was 2018). In induced pluripotent stem cells (iPSC) observed after cisplatin treatment in testicular germ PHLDA3 was expressed at a lower level and reduced cell-derived human embryonal carcinoma cells that gradually during the process of iPSCs generation; PHLDA3 and other genes downstream targets of reprogramming efficiency was inhibited by TP53 are involved in response to DNA damage and PHLDA3 overexpression. Evidence supports that the events leading to cell death (Kerley-Hamilton et al., mechanism by which PHLDA3 promotes decrease 2005). PHLDA3 was identified as a gene modulated iPSC generation efficiency involves Akt- GSK3B by ochratoxin A (OTA) induced genotoxicity, it was activation during the reprogramming process (Qiao upregulated in renal outer medulla cells after et al., 2017). Photoreceptor injury induced PHLDA3 treatment with the renal carcinogen OTA in response
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PHLDA3 (Pleckstrin Homology-Like Domain, family A, Ferreira MP, Nagai MA member 3)
to DNA damage. In other toxicogenomics studies, and associated with pancreatic neuroendocrine PHLDA3 was also proposed as a potential biomarker tumors at an advanced stage, whereas lack of LOH (Uehara et al., 2008; Ellinger-Ziegelbauer et al., was related to lower tumor grades (Ohki et al., 2014; 2008; Hibi et al., 2013; Furihata et al., 2018). Takikawa Ohki, 2017). Fusion genes Also, loss of PHLDA3 associated with protein PHLDA3/ MYBPH (1q32.1/1q32.1). Cancer type: expression downregulation is frequently found in Breast Cancer (FusionGDB ID: 26994). primary lung cancer (Kawase, T. et al., 2009). PHLDA3/ PFKM (1q32.1/ 12q13.11) Cancer type Reduced expression of PHLDA3 is also found in NOS (FusionGDB ID: 26995). 22% of prostate cancers (Soung, et al., 2011). Prostate cancer Furthermore, Low PHLDA3 expression is associated with poor prognosis and postoperative tumor The association of PHLDA3 and prognosis of cancer progression and recurrence in patients with patients is still under investigation. Some studies oesophageal squamous cell carcinoma (ESCC) have found that downregulation of PHLDA3 in (Muroi, et al., 2015). cancer worsens the prognosis of patients diagnosed with cancer. In prostate cancers, for example, reduced expression of PHLDA3 is found in 22% of References the patients in the study. Furthermore, microarray Apostolidis PA, Lindsey S, Miller WM, Papoutsakis ET. analysis performed to evaluate the global Proposed megakaryocytic regulon of p53: the genes methylation profiling of prostate cancer patients with engaged to control cell cycle and apoptosis during megakaryocytic differentiation. Physiol Genomics. 2012 Jun clinical recurrence revealed significant DNA 15;44(12):638-50 methylation of PHLDA3 in the patients with clinical Christgen M, Noskowicz M, Heil C, Schipper E, Christgen recurrence (Mahapatra et al., 2012). H, Geffers R, Kreipe H, Lehmann U. IPH-926 lobular breast Solid cancers (prostate cancer, cancer cells harbor a p53 mutant with temperature-sensitive functional activity and allow for profiling of p53-responsive breast cancer, pancreatic cancer and genes. Lab Invest. 2012 Nov;92(11):1635-47 lung neuroendocrine tumors, lung Day KR, Jagadeeswaran P. Microarray analysis of cancer, gastric cancer, melanoma, prothrombin knockdown in zebrafish. Blood Cells Mol Dis. sarcomas, ovarian cancer, and 2009 Sep-Oct;43(2):202-10 Ellinger-Ziegelbauer H, Gmuender H, Bandenburg A, Ahr colorectal cancer). HJ. Prediction of a carcinogenic potential of rat Prognosis: hepatocarcinogens using toxicogenomics analysis of short- The association of PHLDA3 and prognosis of cancer term in vivo studies. Mutat Res. 2008 Jan 1;637(1-2):23-39 patients is still under investigation. Some studies Fagerberg L, Hallström BM, Oksvold P, Kampf C, have found that downregulation of PHLDA3 in Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, cancer worsens the prognosis of patients diagnosed Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, with cancer. Microarray analysis to evaluate a global Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson methylation profiling of prostate cancer patients with F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, clinical recurrence revealed significant DNA Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten methylation of PHLDA3 in the patients with clinical F, Uhlén M. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics recurrence (Mahapatra et al 2012). and antibody-based proteomics. Mol Cell Proteomics. 2014 In silico analysis using Oncomine datasets showed Feb;13(2):397-406 that underexpression of PHLDA3 together with Frank D, Mendelsohn CL, Ciccone E, Svensson K, Ohlsson INPP5D, SULF2, BTG2, CYFIP2 and KANK3, a R, Tycko B. A novel pleckstrin homology-related gene family hypoxia-inducible TP53-dependent group of genes, defined by Ipl/Tssc3, TDAG51, and Tih1: tissue-specific was significantly associated with a poor clinical expression, chromosomal location, and parental imprinting. Mamm Genome. 1999 Dec;10(12):1150-9 outcome in patients with breast, lung, gastric, melanoma, sarcoma, ovarian, and colorectal cancers. Furihata C, Toyoda T, Ogawa K, Suzuki T. Using RNA-Seq Individually no relation of their expression with with 11 marker genes to evaluate 1,4-dioxane compared with typical genotoxic and non-genotoxic rat patient prognosis was observed, suggesting that their hepatocarcinogens. Mutat Res Genet Toxicol Environ concomitant regulation is the relevant factor for Mutagen. 2018 Oct;834:51-55 clinical outcome in these tumors. A meta-analysis on Han CY, Lim SW, Koo JH, Kim W, Kim SG. PHLDA3 METABRIC data confirmed that lower expression overexpression in hepatocytes by endoplasmic reticulum of these group of genes correlated with TP53 stress via IRE1-Xbp1s pathway expedites liver injury. Gut. mutation status and was associated with poor patient 2016 Aug;65(8):1377-88 outcome in overall survival over 12 years in breast Hibi D, Kijima A, Kuroda K, Suzuki Y, Ishii Y, Jin M, cancer patients (Leszczynska et al., 2015). Nakajima M, Sugita-Konishi Y, Yanai T, Nohmi T, Nishikawa Furthermore, PHLDA3 downregulation was A, Umemura T. Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression consistently observed in cells with PHLDA3 LOH analysis suggests induction of DNA double-strand breaks
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and cell cycle progression. J Toxicol Sci. 2013 Pimkhaokham A, Shimada Y, Fukuda Y, Kurihara N, Imoto Feb;38(1):57-69 I, Yang ZQ, Imamura M, Nakamura Y, Amagasa T, Inazawa J. Nonrandom chromosomal imbalances in esophageal Kawase T, Ohki R, Shibata T, Tsutsumi S, Kamimura N, squamous cell carcinoma cell lines: possible involvement of Inazawa J, Ohta T, Ichikawa H, Aburatani H, Tashiro F, the ATF3 and CENPF genes in the 1q32 amplicon Jpn J Taya Y. PH domain-only protein PHLDA3 is a p53-regulated Cancer Res 2000 Nov;91(11):1126-33 repressor of Akt Cell 2009 Feb 6;136(3):535-50 Qiao M, Wu M, Shi R, Hu W. PHLDA3 impedes somatic cell Kerley-Hamilton JS, Pike AM, Li N, DiRenzo J, Spinella MJ. reprogramming by activating Akt-GSK3β pathway Sci Rep A p53-dominant transcriptional response to cisplatin in 2017 Jun 6;7(1):2832 testicular germ cell tumor-derived human embryonal carcinoma Oncogene 2005 Sep 8;24(40):6090-100 Sakai N, Kajiyama Y, Iwanuma Y, Tomita N, Amano T, Isayama F, Ouchi K, Tsurumaru M. Study of abnormal Korthuis PM, Berger G, Bakker B, Rozenveld-Geugien M, chromosome regions in esophageal squamous cell Jaques J, de Haan G, Schuringa JJ, Vellenga E, Schepers carcinoma by comparative genomic hybridization: H. CITED2-mediated human hematopoietic stem cell relationship of lymph node metastasis and distant maintenance is critical for acute myeloid leukemia Leukemia metastasis to selected abnormal regions Dis Esophagus 2015 Mar;29(3):625-35 2010 Jul;23(5):415-21 Koso H, Tsuhako A, Lai CY, Baba Y, Otsu M, Ueno K, Sakata N, Yamaguchi Y, Chen Y, Shimoda M, Yoshimatsu Nagasaki M, Suzuki Y, Watanabe S. Conditional rod G, Unno M, Sumi S, Ohki R. Pleckstrin homology-like photoreceptor ablation reveals Sall1 as a microglial marker domain family A, member 3 (PHLDA3) deficiency improves and regulator of microglial morphology in the retina Glia islets engraftment through the suppression of hypoxic 2016 Nov;64(11):2005-24 damage PLoS One 2017 Nov 9;12(11):e0187927 Lee CG, Kang YJ, Kim HS, Moon A, Kim SG. Phlda3, a Saxena A, Morozov P, Frank D, Musalo R, Lemmon MA, urine-detectable protein, causes p53 accumulation in renal Skolnik EY, Tycko B. Phosphoinositide binding by the tubular cells injured by cisplatin Cell Biol Toxicol 2015 pleckstrin homology domains of Ipl and Tih1 J Biol Chem Apr;31(2):121-30 2002 Dec 20;277(51):49935-44 Lee CG, Kim JG, Kim HJ, Kwon HK, Cho IJ, Choi DW, Lee Suenaga K, Takasawa H, Watanabe T, Wako Y, Suzuki T, WH, Kim WD, Hwang SJ, Choi S, Kim SG. Discovery of an Hamada S, Furihata C. Differential gene expression integrative network of microRNAs and transcriptomics profiling between genotoxic and non-genotoxic changes for acute kidney injury Kidney Int 2014 hepatocarcinogens in young rat liver determined by Nov;86(5):943-53 quantitative real-time PCR and principal component Leszczynska KB, Foskolou IP, Abraham AG, Anbalagan S, analysis Mutat Res 2013 Feb 18;751(1):73-83 Tellier C, Haider S, Span PN, O'Neill EE, Buffa FM, Takikawa M, Ohki R. A vicious partnership between AKT Hammond EM. Hypoxia-induced p53 modulates both and PHLDA3 to facilitate neuroendocrine tumors Cancer apoptosis and radiosensitivity via AKT J Clin Invest 2015 Sci 2017 Jun;108(6):1101-1108 Jun;125(6):2385-98 Uehara T, Hirode M, Ono A, Kiyosawa N, Omura K, Shimizu Mahapatra S, Klee EW, Young CY, Sun Z, Jimenez RE, T, Mizukawa Y, Miyagishima T, Nagao T, Urushidani T. A Klee GG, Tindall DJ, Donkena KV. Global methylation toxicogenomics approach for early assessment of potential profiling for risk prediction of prostate cancer Clin Cancer non-genotoxic hepatocarcinogenicity of chemicals in rats Res 2012 May 15;18(10):2882-95 Toxicology 2008 Aug 19;250(1):15-26 Mattes K, Berger G, Geugien M, Vellenga E, Schepers H. Wang X, Li J, Yang Z, Wang L, Li L, Deng W, Zhou J, Wang CITED2 affects leukemic cell survival by interfering with p53 L, Xu C, Chen Q, Wang QK. phlda3 overexpression impairs activation Cell Death Dis 2017 Oct 26;8(10):e3132 specification of hemangioblasts and vascular development Muroi H, Nakajima M, Satomura H, Takahashi M, FEBS J 2018 Nov;285(21):4071-4081 Yamaguchi S, Sasaki K, Yokobori T, Miyazaki T, Kuwano Yoo NJ, Kim YR, Lee SH. Expressional and mutational H, Kato H. Low PHLDA3 expression in oesophageal analysis of PHLDA3 gene in common human cancers squamous cell carcinomas is associated with poor Pathology 2011 Aug;43(5):510-1 prognosis Anticancer Res 2015 Feb;35(2):949-54 Ohki R, Saito K, Chen Y, Kawase T, Hiraoka N, Saigawa R, This article should be referenced as such: Minegishi M, Aita Y, Yanai G, Shimizu H, Yachida S, Sakata Ferreira MP, Nagai MA. PHLDA3 (Pleckstrin Homology- N, Doi R, Kosuge T, Shimada K, Tycko B, Tsukada Like Domain, family A, member 3). Atlas Genet T, Kanai Y, Sumi S, Namiki H, Taya Y, Shibata T, Cytogenet Oncol Haematol. 2020; 24(1):8-12. Nakagama H. PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors Proc Natl Acad Sci U S A 2014 Jun 10;111(23):E2404-13
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OPEN ACCESS JOURNAL INIST-CNRS
Gene Section Review
SREBF1 (sterol regulatory element binding transcription factor 1) Seher Gök Scientific and Technological Research Council of Turkey; Ankara-TURKEY/ [email protected]
Published in Atlas Database: February 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/SREBF1ID42386ch17p11.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70643/02-2019-SREBF1ID42386ch17p11.pdf DOI: 10.4267/2042/70643 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Local order SREBF1 spans 26,619 bp, starts at 17811349 and Review on SREBF1, with data on DNA, on the ends at 17837011 bp from pter (according to hg38- protein encoded and where the gene is implicated. Dec_2013). Keywords SREBF1; Streol regulatory element binding DNA/RNA transcription factor 1 Identity Description Orientation: Minus strand; 25669 bp; Exon count: Other names: SREBP1, bHLHd1, SREBP-1c, 22; intron count: 20 SREBP1a HGNC (Hugo): SREBF1 Transcription Location: Located on 17p11.2 SREBF1 gene has 23 transcripts (Table 1)
Figure 1. Gene neighbours of LIPE on chromosome 17p11.2 (Chromosome 17 - NC_000017.11 Reference: GRCh38.p12 current assembly, NCBI Annotation Release 109).
Figure 2. Genomic organization of the SREBF1 gene. Exons are numbered indicating the alternatively spliced a' and c' variants (adapted from Kedenko et al., 2012).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 13 SREBF1 (sterol regulatory element binding transcription Gök S factor 1)
Name Transcript ID bp Protein Biotype Protein SREBF1-201 ENST00000261646.9 4178 1147 coding Protein SREBF1-202 ENST00000355815.8 4253 1177 coding Nonsense SREBF1-203 ENST00000395751.8 4653 216 mediated decay Nonsense SREBF1-204 ENST00000395756.5 3026 113 mediated decay Protein SREBF1-205 ENST00000395757.5 3696 893 coding Protein SREBF1-206 ENST00000423161.3 1058 325 coding No Retained SREBF1-207 ENST00000447641.5 644 protein intron Figure 3. Co-crystal structure of sterol regulatory element No Retained SREBF1-208 ENST00000469356.3 1323 protein intron binding protein 1a bound to an LDL Receptor promoter at 2.3 A resolution (adapted from Párraga et al., 1998). No Retained SREBF1-209 ENST00000470247.1 374 Protein intron Description No Retained SREBF1-210 ENST00000471445.5 936 protein intron The encoded protein is synthesized as a precursor No Retained that is initially attached to the nuclear membrane and SREBF1-211 ENST00000476994.1 591 protein intron endoplasmic reticulum. After cleavage, the mature Protein SREBF1-212 ENST00000478616.1 882 163 protein translocates to the nucleus and activates coding transcription. This cleaveage is inhibited by sterols. Nonsense Alternative promoter usage and splicing result in SREBF1-213 ENST00000485080.6 1230 110 mediated decay multiple transcript variants. 6 isoforms are Protein described. Isoform 1A has been choosen as the SREBF1-214 ENST00000486311.5 473 157 coding canonical sequence (provided by RefSeq, Nov No Retained 2017). Quaternary structure of protein forms a tight SREBF1-215 ENST00000487401.1 477 protein intron complex with SCAP in the ER membrane. Efficient No Retained SREBF1-216 ENST00000490796.1 698 DNA binding of the soluble transcription factor protein intron fragment requires dimerization with another bHLH Protein SREBF1-217 ENST00000577897.1 536 66 coding protein. Interacts with LMNA. Interacts with CEBPA, the interaction produces a transcriptional Protein SREBF1-218 ENST00000578469.1 588 31 coding synergy (By similarity). No Retained Post-translational modifications: SREBF1-219 ENST00000580540.1 540 protein intron At low cholesterol the SCAP/SREBP complex is No Retained SREBF1-220 ENST00000581707.1 695 recruited into COPII vesicles for export from the ER. protein intron In the Golgi complex SREBPs are cleaved No Retained SREBF1-221 ENST00000583080.1 482 sequentially by site-1 and site-2 protease. The first protein intron cleavage by site-1 protease occurs within the luminal No Processed SREBF1-222 ENST00000583732.1 580 protein transcript loop, the second cleavage by site-2 protease occurs within the first transmembrane domain and releases No Retained SREBF1-223 ENST00000584760.1 564 protein intron the transcription factor from the Golgi membrane. Table 1. Transcripts of human SREBF1 gene (Ensembl Apoptosis triggers cleavage by the cysteine annotation Release 85). proteases CASP3 and CASP7 (caspase-3 and caspase-7). Protein Phosphorylated by AMPK (Protein kinase AMP- activated catalytic subunits), leading to suppress SREBF1 gene encodes 1147 amino acid sized protein processing and nuclear translocation, and protein which has 121675 Da molecular mass. repress target gene expression. Phosphorylation at SREBF1 is helix-loop-helix transcriptional activator Ser-402 by SIK1 represses activity possibly by required for lipid homeostasis (Figure 3). Regulates inhibiting DNA-binding. transcription of the LDL receptor gene as well as the Ubiquitinatylated at Lys347, Lys379, Lys587, fatty acid and cholesterol synthesis pathways. Binds Lys675, Lys934, Lys1070. to the sterol regulatory element 1 (SRE-1) (5'- ATCACCCCAC-3'). Has dual sequence specificity Expression binding to both an E-box motif (5'-ATCACGTGA- Expressed in a wide variety of tissues, most 3') and to SRE-1 (5'-ATCACCCCAC-3'). abundant in fat and adrenal gland. In fetal tissues,
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SREBF1 (sterol regulatory element binding transcription Gök S factor 1)
lung and liver shows highest expression. Isoform Somatic SREBF-1C predominates in liver, adrenal gland and 4 SNPs were registered for SREBF1 (according to ovary, whereas isoform SREBF-1A predominates in SNPedia and Human Gene Mutation Database). hepatoma cell lines. Isoform SREBF-1A and isoform SREBF-1C are found in kidney, brain, white fat, and muscle. Implicated in Localisation Endometrial Cancer (EC) Endoplasmic reticulum membrane, golgi membrane, Higher level of SREBF1 has been detected in EC nuclear envelope, nucleoplasm, nucleus, COPII - cells compared to the normal endometrium, and coated vesicle membrane. which was more prominent in higher-grade EC. NP (rs2297508) of SREBF-1 may serve as a genetic Function predisposition factor for the development of EC Qui SREBF1 Transcription factor binds to the sterol et al., 2014). regulatory element-1 (SRE1) (5-ATCACCCCAC-3) which is a motif found in the promoter of the low Pancreatic Cancer density lipoprotein receptor genes and other genes SREBF1 is highly expressed in pancreatic ductal that involved in sterol biosynthesis. cancer. The expression of SREBF1 is an independent Depletion of cholesterol leads to intra-membrane risk factor affecting the overall survival of patients proteolysis, releasing the active portion of SREBF1 with pancreatic cancer (Sun et al., 2015. containing the basic DNA-binding region from the endoplasmic reticulum membrane. Hepatocellular Carcinoma (HCC) After translocation to the nucleus and binding to its SREBF1 expression is activated in HCC. specific DNA sequences, SREBF1 dimers induce the Suppression of SREBF1 induced growth arrest and expression of target genes involved in adipogenesis apoptosis whereas overexpression of SREBF1 and membrane biogenesis (Nohturfft and Zhang, enhanced cell proliferation in human HCC cell lines. 2009). There are a significant relationship between poor survival and high SREBF1 protein expression and Homology correlation between high SREBF1 protein SREBF1 gene is conserved in chimpanzee, Rhesus expression and high risk of mortality with statistical monkey, dog, cow, mouse, rat, chicken, zebrafish, significance (Yamashita et al., 2008). fruit fly, mosquito and frog (Table 2). Ovarian Cancer Gene Identity %& SREBF1 protein expression was significantly higher Species Symbol Protein DNA in human ovarian cancer compared to benign and H. Sapiens SREBF1 borderline ovarian tumors (Nie et al., 2013). vs. P.troglodytes SREBF1 98.7 99.0 Breast cancer vs. M.mulatta SREBF1 97.5 97.1 mRNA levels for SREBF-1c increase in a panel of vs. C.lupus SREBF1 87.9 87.2 primary human breast cancer samples (Yang et al., vs. B.taurus SREBF1 84.5 85.8 2003). vs. M.musculus Srebf1 81.2 80.9 Colorectal Carcinoma vs. R.norvegicus Srebf1 81.6 82.0 SREBF1 and FAS expression upregulated in vs. G.gallus SREBF1 65.8 69.5 colorectal carcinoma cells. It was hypothesized that, vs. X.tropicalis srebf1 67.0 65.9 tumor cells recognize and respond to a deficiency in vs D.reriro srebf1 61.3 62.4 endogenous fatty acid synthesis by upregulating both vs D.melanogaster HLH106 37.5 48.4 SREBF1 and FAS expression and these findings support the model that SREBF1 participates in the vs. A.gambiae AgaP_AGAP000076 39.2 49.7 transcriptional regulation of lipogenic genes in Table 2. Pairwise alignment of SREBF1 gene and protein sequences (in distance from human). colorectal neoplasia (Li et al., 2000). Mutations Obesity and Obesity-related metabolic traits; Type 2 diabetes and 304 missense, 36 truncating and 3 inframe and 7 Dyslipidemia other mutations of SREBF1 was identified in 74247 The SREBF1 molecular screening of 40 unrelated samples from 240 studies (cBioPortal) (Figure 4). obese patients revealed 19 single nucleotide polymorphisms (SNPs).
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SREBF1 (sterol regulatory element binding transcription Gök S factor 1)
Figure 4. Mutation types observed in SREBF1 expression in literature and corresponding color codes are as follows: Green: Missense Mutations ; Black: Truncating Mutations: Nonsense, Nonstop, Frameshift deletion, Frameshift insertion, Splice site; Beige: In-frame Mutations: In-frame deletion, In-frame insertion ; Purple: Other Mutations: All other types of mutations.
SNP17 (54G/C, exon 18c) is associated with morbid Eberlé D, Clément K, Meyre D, Sahbatou M, Vaxillaire M, obesity. SNP3 (-150G/A, exon 1a), SNP5 (-36delG, Le Gall A, Ferré P, Basdevant A, Froguel P, Foufelle F. SREBF-1 gene polymorphisms are associated with obesity exon 1a), and SNP17 are found in high linkage and type 2 diabetes in French obese and diabetic cohorts. disequilibrium (D' > 0.8). The haplotype including Diabetes. 2004 Aug;53(8):2153-7 wild-type alleles of these SNPs (C/G/G/T/C/G, Kedenko L, Lamina C, Kiesslich T, Kapur K, Bergmann S, HAP2) is identified as a risk factor for morbid Waterworth D, Heid IM, Wichmann HE, Kedenko I, obesity (P = 0.003). Kronenberg F, Paulweber B. Genetic polymorphisms of the In the obese group, SNP3, SNP5, and SNP17 are main transcription factors for adiponectin gene promoter in regulation of adiponectin levels: association analysis in associated with male-specific hypertriglyceridemia three European cohorts. PLoS One. 2012;7(12):e52497 (P = 0.07, P = 0.01, and P = 0.05, respectively). SNP17 is also associated with type 2 diabetes (P = Li JN, Mahmoud MA, Han WF, Ripple M, Pizer ES. Sterol regulatory element-binding protein-1 participates in the 0.03) (Eberlé et al., 2004). In addition, it was shown regulation of fatty acid synthase expression in colorectal that insulin induces SREBF1 gene expression in neoplasia. Exp Cell Res. 2000 Nov 25;261(1):159-65 isolated human adipocytes and skeletal muscle and Nie LY, Lu QT, Li WH, Yang N, Dongol S, Zhang X, Jiang also promotes SREBF1 cleavage in human isolated J. Sterol regulatory element-binding protein 1 is required for adipocytes. Common insulin-resistant states, such as ovarian tumor growth Oncol Rep 2013 Sep;30(3):1346-54 obesity and type 2 diabetes, are characterized by decreased expression of SREBP1c mRNA (Sewter et al., 2002). Nohturfft A, Zhang SC. Coordination of lipid metabolism in membrane biogenesis Annu Rev Cell Dev Biol 2009;25:539-66
Párraga A, Bellsolell L, Ferré-D'Amaré AR, Burley SK. Co- References crystal structure of sterol regulatory element binding protein 1a at 2 3 A resolution Structure
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SREBF1 (sterol regulatory element binding transcription Gök S factor 1)
Qiu CP, Lv QT, Dongol S, Wang C, Jiang J. Single Yamashita T, Honda M, Takatori H, Nishino R, Minato H, nucleotide polymorphism of SREBF-1 gene associated with an increased risk of endometrial cancer in Chinese women Takamura H, Ohta T, Kaneko S. Activation of lipogenic PLoS One 2014 Mar 10;9(3):e90491 pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma J Hepatol 2009 Sewter C, Berger D, Considine RV, Medina G, Rochford J, Jan;50(1):100-10 Ciaraldi T, Henry R, Dohm L, Flier JS, O'Rahilly S, Vidal- Puig AJ. Human obesity and type 2 diabetes are associated Yang Yu, Morin PJ, Han WF, Chen T, Bornman DM, with alterations in SREBP1 isoform expression that are Gabrielson EW, Pizer ES. Regulation of fatty acid synthase reproduced ex vivo by tumor necrosis factor-alpha Diabetes expression in breast cancer by sterol regulatory element 2002 Apr;51(4):1035-41 binding protein-1c Exp Cell Res 2003 Jan 15;282(2):132-7 Sun Y, He W, Luo M, Zhou Y, Chang G, Ren W, Wu K, Li This article should be referenced as such: X, Shen J, Zhao X, Hu Y. SREBP1 regulates Gök S. SREBF1 (sterol regulatory element binding tumorigenesis and prognosis of pancreatic cancer through transcription factor 1). Atlas Genet Cytogenet Oncol targeting lipid metabolism Tumour Biol 2015 Haematol. 2020; 24(1):13-17. Jun;36(6):4133-41
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 17 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Review FANCB (FA complementation group B) Sylvie van Twest, Andrew Deans St Vincent's Institute of Medical Research, 9 Princes St, Fitzroy VIC 3065, Australia; [email protected]; [email protected]
Published in Atlas Database: February 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/FANCBID49864chXp22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70644/02-2019-FANCBID49864chXp22.pdf DOI: 10.4267/2042/70644 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract HGNC (Hugo): FANCB Location : Xp22.2 FANCB protein is a component of the Fanconi Anemia (FA) core complex needed for DNA repair. Location (base pair) Within the core complex, FANCB forms a protein FANCB is located on the X chromosome between subcomplex with two other proteins, FAAP100, and base pairs 14,690,863 to 14,873,255 at position an E3 RING ligase FANCL (BL100) to Xp22.2 on the short arm (p) of the X chromosome. monoubiquitinate FANCD2 and FANCI (ID2), a process that is defective in 95% of all FA patients. DNA/RNA FA is a rare, genetic cancer pre-disposition Description syndrome characterized by chromosomal instability and hypersensitivity to DNA crosslinking agents, FANCB has 10 exons, and the translation start site is such as those used in chemotherapy like mitomycin in exon 3 (Meetei et al., 2004). C (MMC) (Kennedy D'Andrea, 2006). FANCB is Transcription the only known X-linked FA gene, and mutations account for 1% of FA cases (Alter Rosenberg, The FANCB gene undergoes X-inactivation. 2013). The mutated FANCB allele is preferentially Keywords: FANCB, Fanconi Anemia; inactivated in female carriers (so the wild-type allele Ubiquitination, VACTERL-H; Cancer pre- is expressed), while males with mutations in FANCB disposition; Chromosome X get FA (Meetei et al., 2004). FANCB linked FA accounts for 1% of FA cases, and Identity only affects male patients. Other names: FAB, FA2, FACB
Figure 1: Genomic context of FANCB on chromosome (Adapted from NCBI).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 18 FANCB (FA complementation group B) van Twest S, Deans A
Figure 2: Schematic of FANCB gene. Black represents exons (protein coding regions), white represents introns (non-coding). Adapted from McCauley et al. 2011.
BioProject PRJNA270632 looked at tissue specific Protein FANCB RNA induction during human fetal development from 6 tissues between 10-20 weeks Description gestational time. The FANCB gene encodes FANCB protein comprised of 859 amino acids, with a molecular Function mass of 97726 Da. It has a putative C-terminal FANCB is a component of the Fanconi Anemia 9 nuclear localization signal (Meetei et al., 2004). protein "core complex" that acts as a multiunit ubiquitin ligase to ubiquitinate FANCD2 and FANCI in response to DNA damage incurred during DNA replication in S-phase, or to detection of interstand cross links (ICL) (Ceccaldi, Sarangi, D'Andrea, 2016). The key event in the FA pathway is the monoubiquitination of ID2 that activates downstream DNA repair proteins. The core complex is comprised of 3 separate sub- complexes, , FANCG, FAAP20 (AG20), FANCC, FANCE, FANCF (CEF), and FANCB, FANCL, FAAP100 (BL100) (Huang et al., 2014; Medhurst et al., 2006). The BL100 sub-complex is critical to core
Figure 3: The 9 protein core complex associates in 3 complex assembly as it forms a bridge between distinct subcomplexes: AG20 (FANC A, G, FAAP20), AG20 and CEF (van Twest et al., 2017). The BL100 BL100 (FANC B, L, FAAP100), and CEF (FANC C,E,F). subcomplex is dimeric, and FANCB homodimer Dashed lines indicate groupings of sub-complexes, while triple lines indicate putative direct protein interactions. forms the interface between two copies of FANCL (a RING E3 ligase), and FAAP100 to simultaneously Expression ubiquitinate FANCD2 and FANCI (ID2) (Swuec et Low expression in tissues. Results from Illumina al., 2016; van Twest et al., 2017). Correspondingly, bodyMap2 transcriptome (BioProject: PRJEB2445) FANCB and FAAP100 stabilize FANCL (Rajendra of high throughput sequencing of individual and et al., 2014), and enhance its activity by 5-fold in mixture of 16 human tissue RNA showed highest invitro assays (Ling et al., 2007). Mutation in any expression in white blood cells (mean RPKM 0.32), one of the 19 FA genes results in defective DNA testes (mean RPKM 0.23), brain (mean RPKM repair. 0.168), adrenal (mean RPKM 0.164), ovary (mean RPKM 0.153), and lymph nodes (mean PRKM Mutations 0.149). Another RNA sequencing project of total RNA from 20 human tissues (BioProject: Somatic PRJNA280600) found highest FANCB expression Somatic FANCB mutations are very rare, and may in brain cerebellum (mean RPKM 0.789), and occur at normal mutagenesis rate. Small insertions, thymus (mean RPKM 0.524). point mutations, and large deletions have been BioProject PRJEB4337 performed HPA RNA reported in the FANCB gene (McCauley et al., 2011; sequencing of normal tissues found highest FANCB Meetei et al., 2004). Most FANCB mutations result expression in bone marrow and in lymph nodes. in truncation of the encoded protein.
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FANCB (FA complementation group B) van Twest S, Deans A
Figure 4: Schematic of Fanconi Anemia DNA damage response pathway. In response to interstrand cross links (ICL), or DNA damage from DNA replication, FANCM recruits the 9 protein core complex to DNA damage sites to monoubiquitinate FANC D2 and I. The core complex is comprised of 3 sub-complexes AG20 (FANC A, G, FAAP20), BL100 (FANC B, L, FAAP100), and CEF (FANC C,E,F). Dashed lines indicate groupings of sub-complexes, while triple lines indicate putative direct protein interactions. Within the core complex, FANCL has a RING E3 domain with ubiquitin ligase activity, but mutation in any one of the FA genes leads to defective DNA repair. Ubiquitinated ID2 is activated, and localized to chromatin in nuclear foci to interact with downstream DNA repair proteins (FANCD1, PALB2 (FANCN)) to repair DNA via homologous recombination. Once DNA repair is completed, USP1 deubiquitinates ID2 so that DNA damage response can be reinitiated. Figure adapted from https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/fancb.
Implicated in Fanconi Anemia Disease Mutated FANCB is implicated in Fanconi Anemia (FA), a rare genetic condition that results in progressive bone marrow failure (pancytopenia), congenital malformations in 75% of patients (short stature, urogenital defects, café au lait spots, skeletal malformations), and cancer pre-disposition (primarily acute myeloid leukaemia, and certain solid tumours) (Alter, 2014). As the only X-linked FA gene, FANCB accounts for 1% of FA cases, in all other instances FA is autosomal recessive. Mutations in FANCB (and all other core complex FA proteins) is associated with hypersensitivity to DNA-damaging agents, chromosomal instability with increased chromosome breakage and defective DNA repair. In addition to FA, some patients with FANCB mutations also exhibit hydrocephalus-VACTERL (vertebral, anal, cardiac, tracheo-esophageal fistula, Figure 5: FANCB dimer coordinates FANCD2:FANCI renal, and limb anomalies) syndrome. A frameshift monoubiquitination by two FANCL RING-ligases. FANCB mutation that results in a truncated protein (stop codon at position 446) was associated with
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FANCB (FA complementation group B) van Twest S, Deans A
VACTERL-H (Holden et al., 2006; McCauley et al., Kennedy RD, D'Andrea AD. DNA repair pathways in clinical 2011). practice: lessons from pediatric cancer susceptibility syndromes J Clin Oncol 2006 Aug 10;24(23):3799-808 Prognosis The prognosis for FA is poor as there is no cure, and Ling C, Ishiai M, Ali AM, Medhurst AL, Neveling K, Kalb R, Yan Z, Xue Y, Oostra AB, Auerbach AD, Hoatlin ME, the average lifespan is 20-30 years. Schindler D, Joenje H, de Winter JP, Takata M, Meetei AR, If no congenital abnormalities are apparent at birth, Wang W. FAAP100 is essential for activation of the Fanconi patients are often diagnosed with FA when they anemia-associated DNA damage response pathway EMBO present with aplastic anemia ages 8-10 (>700 fold J 2007 Apr 18;26(8):2104-14 risk) (Alter, 2014). McCauley J, Masand N, McGowan R, Rajagopalan S, Bone marrow transplants are often conducted to Hunter A, Michaud JL, Gibson K, Robertson J, Vaz F, Abbs correct the haematological issues associated with S, Holden ST. X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FA, however due to faulty DNA repair FA patients FANCB mutations Am J Med Genet A 2011 retain high cancer risk particularly leukaemia, and Oct;155A(10):2370-80 head and neck squamous cell carcinomas Medhurst AL, Laghmani el H, Steltenpool J, Ferrer M, (approximately 500 fold risk) (Shimamura Alter, Fontaine C, de Groot J, Rooimans MA, Scheper RJ, Meetei 2010). AR, Wang W, Joenje H, de Winter JP. Evidence for Diagnostic subcomplexes in the Fanconi anemia pathway Blood 2006 Diagnostics for FA is done with a chromosomal Sep 15;108(6):2072-80 breakage test; when treated with interstand Pagel PS, Kampine JP, Schmeling WT, Warltier DC. crosslinking agents such as mitomycin C (MMC) or Ketamine depresses myocardial contractility as evaluated by the preload recruitable stroke work relationship in diepoxybutane (DEB) FA cells exhibit high number chronically instrumented dogs with autonomic nervous chromosomal breakages, and abnormalities as system blockade Anesthesiology 1992 Apr;76(4):564-72 compared to normal cells. Rajendra E, Oestergaard VH, Langevin F, Wang M, Dornan GL, Patel KJ, Passmore LA. The genetic and biochemical References basis of FANCD2 monoubiquitination Mol Cell 2014 Jun 5;54(5):858-69 Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Swuec P, Renault L, Borg A, Shah F, Murphy VJ, van Twest Hematol Educ Program. 2007;:29-39 S, Snijders AP, Deans AJ, Costa A. The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Alter BP, Rosenberg PS. VACTERL-H Association and Symmetric Mono-ubiquitination of FANCI-FANCD2 Cell Fanconi Anemia. Mol Syndromol. 2013 Feb;4(1-2):87-93 Rep 2017 Jan 17;18(3):611-623 Ceccaldi R, Sarangi P, D'Andrea AD. The Fanconi anaemia van Twest S, Murphy VJ, Hodson C, Tan W, Swuec P, pathway: new players and new functions. Nat Rev Mol Cell O'Rourke JJ, Heierhorst J, Crismani W, Deans AJ. Biol. 2016 Jun;17(6):337-49 Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway Mol Cell 2017 Jan 19;65(2):247- Frischknecht W. [Early determination of handicaps in the 259 newborn and infants] Schweiz Rundsch Med Prax 1971 Jul 27;60(30):1021-2 . FARF Inc . Fanconi Anemia: Guidelines for Diagnosis and Management. Eugene, OR Fanconi Anemia Research Holden ST, Cox JJ, Kesterton I, Thomas NS, Carr C, Woods Fund, Inc; 2014. CG. Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome J Med Genet 2006 Sep;43(9):750-4 This article should be referenced as such: Huang Y, Leung JW, Lowery M, Matsushita N, Wang Y, van Twest S, Deans A. FANCB (FA complementation Shen X, Huong D, Takata M, Chen J, Li L. Modularized group B). Atlas Genet Cytogenet Oncol Haematol. 2020; functions of the Fanconi anemia core complex Cell Rep 24(1):18-21. 2014 Jun 26;7(6):1849-57
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 21 Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS
Gene Section Review
AQP1 (aquaporin 1 (Colton blood group)) Jean Loup Huret [email protected] Published in Atlas Database: February 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/AQP1ID46249ch7p14.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70645/02-2019-AQP1ID46249ch7p14.pdf DOI: 10.4267/2042/70645
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Protein Review on aquaporin-1 (AQP1), with data on DNA, Aquaporins are a family of hydrophobic on the protein encoded, and where the gene is transmembrane channel proteins involved in implicated. transport of water and small molecules in response Keywords to osmotic gradients. They are distributed Aquaporin-1; AQP1; Tissue water balance; Cell throughout many tissues, with various known roles migration; Cell division; Cell adhesion; Cellular of production, secretion, reabsorption and regulation volume regulation; Apoptosis; Angiogenesis; Cell of water, but also of cell migration (angiogenesis), cycle; Cell proliferation; Cell membrane; Channel; signal transduction, and cell proliferation. There are Cell junction; WNT 14 AQPs in humans (and 5 pseudogenes): MIP (previously called AQP0), AQP1, AQP2, AQP3, Identity AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, AQP10, AQP11, AQP12A and AQP12B. They are classified Other names: CHIP28 into two families: orthodox aquaporins, that HGNC (Hugo): AQP1 transport water only, and aquaglyceroporins (AQP3, AQP7 and AQP9), which also transport glycerol, Location : 7p14.3 urea and other small molecules. AQPs form homo- tetramers (Review in Papadopoulos and Saadoun, DNA/RNA 2015). The monomeric units of AQPs are ~30 kDa proteins and consist of 6 transmembrane α-helices Transcription (M1, M2, M4 to M6 and M8), 2 intramembrane half There are various splicing forms. helices (M3 and M7), and 5 connecting loops (loops Canonical form transcript (hg38), including UTRs: A to E) (Review in Verkman et al., 2014). They bear chr7:30,911,694 - 30,925,516, size: 13,823bp on conserved intramembrane Asn-Pro-Ala (NPA) forward (+) strand; coding region: chr7:30,911,910 - sequence motifs in the intramembrane domains, and 30,923,629, size: 11,720bp, according to UCSC. six tilted transmembrane helices per monomer, with Four exons: exon1 (nt 1 - 600) codes for amino acids linkers (loops A to E). The NPA motifs act as (aa) 1-128, exon2 (nt 10373 - 10537) for aa 129-183; hydrogen-bond donors and acceptors that coordinate exon3 (nt 10871 - 10951) for aa 184-210, and exon4 the transport of water through the pore (Verkman et (nt 11757 - 13823) for aa 211-269 (nextProt). al., 2014).
Atlas Genet Cytogenet Oncol Haematol. 2019; 24(1) 22 AQP1 (aquaporin 1 (Colton blood group)) Huret JL
Figure 1. Aquaporin-1 (AQP1) gene exons and protein domains.
Description Aquaporin-1 canonical form: 269 aa; 28.526kDa; 166 (Cytoplasmic ("Loop D")), 167 - 183 other isoforms; 218, 186, and 154 aa. AQP1 is a (Transmembrane), 184 - 186 (Extracellular ("Loop transmembrane protein, with a N-term and a C-term E")), 187 - 200 (Intramembrane), 201 - 207 cytoplasmic domains: amino acids 2 - 7 (Extracellular), 208 - 228 (Transmembrane), 229 - (Cytoplasmic), 8 - 36 (Transmembrane), 37 - 48 269 (Cytoplasmic) (Figure. 1). (Extracellular ("Loop A")), 49 - 66 Helical subunits in Loop B and E juxtapose to form (Transmembrane), 67 - 70 (Cytoplasmic), 71 - 84 a water pore in the monomere. (Intramembrane), 85 - 94 (Cytoplasmic ("Loop B"), The central pore of the homotetramer (Figure. 2) 95 - 115 (Transmembrane), 116 - 136 (Extracellular would be a path for ion and gas (Review in Tomita ("Loop C")), 137 - 155 (Transmembrane), 156 – et al., 2017).
Figure 2. Aquaporins monomere and tetramere. Aquaporins are transmembrane proteins involved in transport of water and small molecules in response to osmotic gradients (water channels).
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AQP1 (aquaporin 1 (Colton blood group)) Huret JL
Erythrocyte: CO2 metabolite enters erythrocytes via diffusion and/or gas channels (e.g. AQP1 and RHAG). AQP1 is a H2O/CO2 channel in the erythrocyte. There are 160,000-200,000 copies of AQP1 on one erythrocyte membrane (Hsu 2018). AQP1 forms complex with SLC4A1 (band 3) and CA2 (carbonic anhydrase II) for intraerythrocytic CO2/HCO3 conversion in relation to desoxy-hemoglobin (Hsu 2018). 60% of CO2 flux in or out of RBCs is via AQP1 gas channel. The rest of CO2 flux is likely through another gas channel, RHAG, and/or direct diffusion (Hsu 2018).
Localisation Figure 3. ModBase predicted comparative 3D structure. Localized to the plasma membrane. Remarkable sites: (Figure. 1) Function NPA: aa 76-78, 192-194 N-myristoylation sites (role in membrane targeting): AQPs main's role is to maintain tissue water balance. aa 30-35, 40-45, 57-62, 82-87, 104-109, 114-119, AQPs also facilitate cell migration, cell proliferation 121-126, 132-137, 136-141, 173-178, 190-195, 219- and cell adhesion. Cell migration: AQPs concentrate 224. at the leading end of migrating cells and facilitate the N-glycosylation sites: aa 42-45, 205-208. formation of the lamellipodium (Papadopoulos and Protein kinase C phosphorylation sites: aa 157 - 159, Saadoun, 2015). Cell proliferation: AQPs may 239-241 (Thr 157 and 239); Casein kinase II activates transduction pathways such as the mitogen- phosphorylation site: aa 262 - 265 (Ser 262). activated protein kinase pathways or the Wnt/ β- Poly Arg (for preventing proton conduction): aa 159- catenin signaling. 162. AQP1 may also be involved in down regulation of apoptosis. AQP1 up-regulation induces CTNNB1 Expression (β-catenin) overexpression and serves as co- AQPs are widely expressed. AQP1 is the main water activator in the nucleus to activate Wnt responsive channel in human (especially erythrocytes), but its genes such as MYC, CCND1 (cyclin D1), JUN and function in water permeation can be alternatively FOSL1. AQP1 stabilises the cadherin/ supported by urea transporters SLC14A1 and CTNNB1/Lin7/F-actin complex to enhance the SLC14A2 and glucose transporter SLC2A1 migratory and invasive capacity of tumor cells. (GLUT1). The CO2-transporting function of APQ1 AQP1 enhances the activity of MMP2 and MMP9 is replaceable by RHAG gas channel. (Hsu 2018). through PTK2 (FAK) and Wnt signalling pathways. AQP1 is expressed in all tissues, in particular in renal Hypoxia induces AQP1 overexpression in tumour tubules, exocrine pancreas, neuropil (synaptically cells, in combination with important downstream dense regions of brain), bile ducts, corneal effectors including CTNNB1, FAK and the Rho endothelium, bone marrow, myoepithelial cells of family of GTPases known for their role in breast and endothelial cells (The Human Protein tumorigenesis. (see review in Tomita et al., 2017). Atlas). AQP1 is present in pleura and microvessels. AQP1 and AQP4 are expressed in the iris and ciliary Mutations epithelium and play important roles in regulating aqueous humor (review in Huber et al. 2012). Germinal Choroid plexus epithelium: AQP1 is highly Polymorphism: AQP1 is responsible for the Colton expressed in the apical side of choroid plexus blood group system, with high incidence of Co(a) epithelium, where it facilitates cerebrospinal fluid allele/antigen (Ala in aa 45), and low incidence of (CSF) secretion and intracranial pressure regulation Co(b) allele/antigen (Val in aa 45). Colton-null (Longatti et al., 2006; review in Huber et al. 2012). phenotype Co(a-b-), is an aquaporin-1 deficiency. Renal proximal tubule and loop of Henle: mice The patients, under stress, have a defect in urinary deficient in AQP1 have a reduced ability to concentration capacity (King et al., 2002). AQP1- concentrate urine and there is also a moderate null mice have a significant decrease in urine defective urinary concentrating ability in AQP1 osmolarity, but a normal survival.
deficient patients (King et al., 2001).
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Epigenetics Colorectal cancer Increased expression of aquaporins 1 and 4 was Aquaporin-1 is an independent prognostic factor in found in Creutzfeldt-Jakob disease (Rodrèguez et al. advanced colon cancer (Yoshida et al., 2013). 2006). Expression of aquaporins 1, 3, and 5 was found in seven colon and colorectal cancer cell lines. The Implicated in expression of aquaporins 1 and 5 was induced in early-stage disease (early dysplasia) and maintained Aquaporin-1 is a well-established marker of through the late stages of colon cancer development proliferating tumor microvessels (Saadoun et al., (Moon et al., 2003). 2002). Aquaporin-1 is present in tumor vascular Head and neck cancer endothelium. AQP-expressing cancer cells show High expression is correlated with better prognosis enhanced migration in vitro and greater local tumor in head and neck cancer, according to The Human invasion, tumor cell extravasation, and metastases in Protein Atlas. On the other hand, aquaporin-1 was vivo than aquaporin-1-null transgenic mice. overexpressed in nasopharyngeal cancer tissues; Aquaporin-1 facilitates endothelial cell migration migrated tumor tissue had even higher expression and angiogenesis. (Li and Zhang 2010). Astrocytoma Hemangioblastoma A t(1;7)(p13;p14) AQP1/ CHI3L2 has been found in Upregulation of aquaporin-1 expression was found low grade astrocytoma (Yoshihara et al., 2015). in hemangioblastoma (Chen et al. 2006). The fusion gene ADCYAP1R1/AQP1 7p14-7p14 Kidney adenocarcinomay has been found in astrocytoma (Hu et al., 2018). There was a significant increase in aquaporin-1 A t(7;20)(p14;q13) AQP1/ ARFGEF2 has been expression from low-grade to high-grade found in adenocarcinoma of the kidney (Hu et al., astrocytomas. AQP1 up-regulation was 2018). predominantly located perivascularly, and High expression is correlated with better prognosis associated with angiogenesis, as well as with in renal cell cancer according to The Human Protein invasion of grade IV astrocytoma (El Hindy et al., Atlas. 2013). Aquaporin-1 was expressed in microvessel Lung cancer endothelia and neoplastic astrocytes in metastatic A t(6;7)(p21;p14) AQP1/ CFB has been found in carcinomas. Aquaporin-1 may participate in the lung adenocarcinoma (Hu et al., 2018). formation of brain tumor edema (Saadoun et al., Aquaporin-1 was overexpressed in adenocarcinoma 2002). and bronchoalveolar carcinoma, respectively, Bladder urothelial carcinoma whereas all cases of squamous cell carcinoma and Marked increase expression levels of aquaporin-1 normal lung tissue were negative (Hoque et al., was noted with bladder urothelial carcinoma 2006). histological grade and pathological stage. The Multiple myeloma expression of aquaporin-1 was markedly higher in Patients with active multiple myeloma display cancerous tissues with lymph node metastasis (Liu et significantly higher levels of aquaporin-1 than those al., 2015). with non-active multiple myeloma. Patients with Breast adenocarcinoma monoclonal gammopathies of undetermined A t(7;19)(p14;p13) AQP1/ TYK2 has been found in significance (MGUS) had lower levels of aquaporin- breast adenocarcinoma (Hu et al., 2018). 1 (Vacca et al. 2001). Aquaporin-1 is thought to be involved in estrogen Uterus cervical carcinoma mediated angiogenesis in the mammary gland The fusion gene TRA2A/AQP1 (7p15-7p14) has (Mobasheri and Barrett-Jolley, 2014). been found in squamous cell carcinoma of the uterus Cholangiocarcinoma cervix (Hu et al., 2018). Strong aquaporin-1 expression predicts poor Aquaporins 1 and 3 were upregulated in cervical survival, regardless of pathological features in hilar carcinoma, significantly increased in advanced stage cholangiocarcinoma (Li et al., 2017). disease, and patients with deeper tumor infiltration, lymph node metastases or larger tumor volume Choroid plexus carcinoma (Chen et al., 2014). Aquaporin-1 plays a role in tumor angiogenesis, cell Uterus endometrial adenocarcinoma migration, extravasation, and metastasis in choroid plexus carcinoma. A positive correlation between aquaporin-1,
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microvascular density and vascular endothelial Huber VJ, Tsujita M, Nakada T. Aquaporins in drug growth factor ( VEGFA) expression in tumor discovery and pharmacotherapy. Mol Aspects Med. 2012 Oct-Dec;33(5-6):691-703 progression of endometrial adenocarcinoma (Pan et al. 2008). Kao SC, Armstrong N, Condon B, Griggs K, McCaughan B, Maltby S, Wilson A, Henderson DW, Klebe S. Aquaporin 1 Pleural malignant mesothelioma is an independent prognostic factor in pleural malignant mesothelioma. Cancer. 2012 Jun 1;118(11):2952-61 Expression of aquaporin-1 in malignant mesothelioma is an independent prognostic factor, King LS, Choi M, Fernandez PC, Cartron JP, Agre P. Defective urinary concentrating ability due to a complete irrespective of the type of treatment received. deficiency of aquaporin-1 N Engl J Med 2001 Jul Expression of AQP1 by more than 50% of tumor 19;345(3):175-9 cells was associated with prolonged survival (Kao et King LS, Nielsen S, Agre P, Brown RH. Decreased al., 2012). pulmonary vascular permeability in aquaporin-1-null Prostate adenocarcinoma humans Proc Natl Acad Sci U S A 2002 Jan 22;99(2):1059- 63 Aquaporin-1 overexpression was significantly King TE Jr. Respiratory bronchiolitis-associated interstitial associated with higher Gleason scores and is lung disease Clin Chest Med 1993 Dec;14(4):693-8 associated with prostate adenocarcinoma progression (Park and Yoon 2017). Li C, Li X, Wu L, Jiang Z. Elevated AQP1 Expression Is Associated With Unfavorable Oncologic Outcome in Patients With Hilar Cholangiocarcinoma Technol Cancer To be noted Res Treat 2017 Aug;16(4):421-427 Aquaporin-targeted drugs: Heavy metal ions Li Q, Zhang B. Expression of aquaporin-1 in nasopharyngeal cancer tissues J Otolaryngol Head Neck (mercury, silver, gold) are inhibitors of aquaporin-1. Surg 2010 Oct;39(5):511-5 The Henle loop diuretic bumetanide and analogues AqB013 and AqF026 also inhibit aquaporin-1. The Liu J, Zhang WY, Ding DG. Expression of aquaporin 1 in bladder uroepithelial cell carcinoma and its relevance to quaternary ammonium compound recurrence Asian Pac J Cancer Prev 2015;16(9):3973-6 tetraethylammonium is an inhibitor of aquaporin-1 Longatti P, Basaldella L, Orvieto E, Dei Tos A, Martinuzzi A. water permeability (Verkman et al., 2014; Tomita et Aquaporin(s) expression in choroid plexus tumours Pediatr al., 2017). Neurosurg 2006;42(4):228-33 Meléndez, Fernádez y Cuxart, Muniesa. [Perspectives of References promotion for current nurses] Caridad Cienc Arte 1970;7(22):7-8 Chen R, Shi Y, Amiduo R, Tuokan T, Suzuk L. Expression and prognostic value of aquaporin 1, 3 in cervical carcinoma Mobasheri A, Barrett-Jolley R. Aquaporin water channels in in women of Uygur ethnicity from Xinjiang, China. PLoS the mammary gland: from physiology to pathophysiology One. 2014;9(2):e98576 and neoplasia J Mammary Gland Biol Neoplasia 2014 Mar;19(1):91-102 Chen Y, Tachibana O, Oda M, Xu R, Hamada J, Yamashita J, Hashimoto N, Takahashi JA. Increased expression of Moon C, Soria JC, Jang SJ, Lee J, Obaidul Hoque M, aquaporin 1 in human hemangioblastomas and its Sibony M, Trink B, Chang YS, Sidransky D, Mao L. correlation with cyst formation. J Neurooncol. 2006 Involvement of aquaporins in colorectal carcinogenesis Dec;80(3):219-25 Oncogene 2003 Oct 2;22(43):6699-703 El Hindy N, Bankfalvi A, Herring A, Adamzik M, Lambertz N, Papadopoulos MC, Saadoun S. Key roles of aquaporins in Zhu Y, Siffert W, Sure U, Sandalcioglu IE. Correlation of tumor biology Biochim Biophys Acta 2015 Oct;1848(10 Pt aquaporin-1 water channel protein expression with tumor B):2576-83 angiogenesis in human astrocytoma. Anticancer Res. 2013 Feb;33(2):609-13 Park JY, Yoon G. Overexpression of Aquaporin-1 is a Prognostic Factor for Biochemical Recurrence in Prostate Hoque MO, Soria JC, Woo J, Lee T, Lee J, Jang SJ, Adenocarcinoma Pathol Oncol Res 2017 Jan;23(1):189- Upadhyay S, Trink B, Monitto C, Desmaze C, Mao L, 196 Sidransky D, Moon C. Aquaporin 1 is overexpressed in lung cancer and stimulates NIH-3T3 cell proliferation and Rodríguez A, Pérez-Gracia E, Espinosa JC, Pumarola M, anchorage-independent growth. Am J Pathol. 2006 Torres JM, Ferrer I. Increased expression of water channel Apr;168(4):1345-53 aquaporin 1 and aquaporin 4 in Creutzfeldt-Jakob disease and in bovine spongiform encephalopathy-infected bovine- Hsu K. Exploring the Potential Roles of Band 3 and PrP transgenic mice Acta Neuropathol 2006 Aquaporin-1 in Blood CO2 Transport-Inspired by Nov;112(5):573-85 Comparative Studies of Glycophorin B-A-B Hybrid Protein GP.Mur. Front Physiol. 2018;9:733 Saadoun S, Papadopoulos MC, Davies DC, Bell BA, Krishna S. Increased aquaporin 1 water channel expression Hu X, Wang Q, Tang M, Barthel F, Amin S, Yoshihara K, in human brain tumours Br J Cancer 2002 Sep 9;87(6):621- Lang FM, Martinez-Ledesma E, Lee SH, Zheng S, Verhaak 3 RGW. TumorFusions: an integrative resource for cancer- associated transcript fusions. Nucleic Acids Res. 2018 Jan Tomita Y, Dorward H, Yool AJ, Smith E, Townsend AR, 4;46(D1):D1144-D1149 Price TJ, Hardingham JE. Role of Aquaporin 1 Signalling in Cancer Development and Progression Int J Mol Sci 2017 Jan 29;18(2)
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Vacca A, Frigeri A, Ribatti D, Nicchia GP, Nico B, Ria R, Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna Svelto M, Dammacco F. Microvessel overexpression of R, Kim H, Verhaak RG. The landscape and therapeutic aquaporin 1 parallels bone marrow angiogenesis in patients relevance of cancer-associated transcript fusions with active multiple myeloma Br J Haematol 2001 Oncogene 2015 Sep 10;34(37):4845-54 May;113(2):415-21 This article should be referenced as such: Verkman AS, Anderson MO, Papadopoulos MC. Aquaporins: important but elusive drug targets Nat Rev Huret JL. AQP1 (aquaporin 1 (Colton blood group)). Drug Discov 2014 Apr;13(4):259-77 Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1):22- 27. Yoshida T, Hojo S, Sekine S, Sawada S, Okumura T, Nagata T, Shimada Y, Tsukada K. Expression of aquaporin- 1 is a poor prognostic factor for stage II and III colon cancer Mol Clin Oncol 2013 Nov;1(6):953-958
Atlas Genet Cytogenet Oncol Haematol. 2019; 24(1) 27 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Review AQP2 (aquaporin 2) Jean Loup Huret [email protected] Published in Atlas Database: March 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/AQP2ID52230ch12q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70646/03-2019-AQP2ID52230ch12q13.pdf DOI: 10.4267/2042/70646 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Protein Review on aquaporin-2 (AQP2), with data on DNA, Aquaporins are a family of hydrophobic on the protein encoded, and where the gene is transmembrane channel proteins involved in implicated. transport of water and small molecules in response Keywords to osmotic gradients. They are distributed Aquaporin-2; AQP2; Tissue water balance; Cell throughout many tissues, with various known roles migration; Cellular volume regulation; Cell of production, secretion, reabsorption and regulation membrane; Channel; Nephrogenic diabetes of water, but also of cell migration (angiogenesis), insipidus; Urine concentration; Collecting duct; signal transduction, and cell proliferation. There are Kidney 14 AQPs in humans (and 5 pseudogenes): MIP (previously called AQP0), AQP1, AQP2, AQP3, Identity AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, AQP10, AQP11, AQP12A and AQP12B. They are classified Other names: AQP-CD, WCH-CD into two families: orthodox aquaporins, that HGNC (Hugo): AQP2 transport water only, and aquaglyceroporins (AQP3, AQP7 and AQP9), which also transport glycerol, Location : 12q13 urea and other small molecules. AQPs form homo- tetramers (Review in Papadopoulos and Saadoun, DNA/RNA 2015). The monomeric units of AQPs are ~30 kDa Transcription proteins and consist of 6 transmembrane α-helices (M1, M2, M4 to M6 and M8), 2 intramembrane half There are various splicing forms. Canonical form helices (M3 and M7), and 5 connecting loops (loops transcript (hg38), including UTRs: A to E) (Review in Verkman et al., 2014). They bear chr12:30,911,694 - 30,925,516, size: 13,823bp on conserved intramembrane Asn-Pro-Ala (NPA) forward (+) strand; coding region: chr12: sequence motifs in the intramembrane domains, and 49,950,746-49,958,881 size: 8,136bp, according to six tilted transmembrane helices per monomer, with UCSC. linkers (loops A to E). The NPA motifs act as Four exons: exon1 (nt 1 - 450) codes for amino acids hydrogen-bond donors and acceptors that coordinate (aa) 1-120, exon2 (nt 3415 - 3579) for aa 121-175; the transport of water through the pore (Verkman et exon3 (nt 3890 - 3970) for aa 176-202, and exon4 (nt al., 2014). 4659 - 8141) for aa 203-271 (nextProt).
Atlas Genet Cytogenet Oncol Haematol. 2019; 24(1) 28 AQP2 (aquaporin 2) Huret JL
Figure 1. Aquaporin-2 (AQP2) gene exons and protein domains.
Description Helical subunits in Loop B and E juxtapose to form a water pore in the monomere. The central pore of Aquaporin-2 canonical form: 271 aa; 28.837kDa; the homotetramer (Figure. 2) would be a path for ion other isoforms; 223, and 244 aa. and gas (Review in Huber et al., 2012). AQP2 is a transmembrane protein, with a N-term Remarkable sites: (Figure. 1) and a C-term cytoplasmic domains: amino acids 1 - NPA: aa 68-70, 184-186 16 (Cytoplasmic), 17 - 34 (Transmembrane), 35 - 40 N-myristoylation sites (role in membrane targeting): (Extracellular ("Loop A")), 41 - 59 aa 27-32, 29-34, 49-54, 78-83, 96-101, 128-133, (Transmembrane), 60 - 85 (Cytoplasmic ("Loop 175-180, 211-216. B")), 86 - 107 (Transmembrane), 108 - 127 N-glycosylation sites: aa 123-126. (Extracellular ("Loop C")), 128 - 148 Protein kinase C phosphorylation sites: aa 195-197, (Transmembrane), 149 - 156 (Cytoplasmic ("Loop 231-233 (Thr 195 and Ser 231); Casein kinase II D")), 157 - 176 (Transmembrane), 177 - 202 phosphorylation site: aa 108-111 (Thr 108), 148-151 (Extracellular ("Loop E")), 203 - 224 (Ser 148), 229-232 (Ser 229), 244-247 (Thr 244); (Transmembrane), 225 - 271 (Cytoplasmic) (Figure. cAMP-and cGMP-dependent protein kinase (PKA) 1). phosphorylation site :aa 253-256.
Figure 2. Aquaporins monomere and tetramere. Aquaporins are transmembrane proteins involved in transport of water and small molecules in response to osmotic gradients (water channels).
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Cell attachment sequence RGD (plays a role in cell binding of vasopressin to AVPR2, the cAMP/PKA adhesion): aa 113-115. (PRKAR1A 387) signal is activated, PRKAR1A is Microbodies C-terminal targeting signal (targeting recruited to the vesicles through PRKAR1A- to organelles such as peroxisomes): aa 269-271. anchoring proteins (AKAPs) (AKAP7 46846 co- Expression localizes with AQP2) and results in phosphorylation in the C-terminus of AQP2 at serines 256, 264, and AQPs are widely expressed. AQP2 is mainly 269, withdrawing it from F-actin. expressed in the kidney. AQP2 is subsequently translocated to the apical Renal collecting duct principal cells plasma membrane, and the water luminal Extra-renal localizations: Ear, epididymis, vas permeability to increase water reabsorption from deferens, vagina. Both AQP1 and AQP2 are urine. Vasopressin also triggers increases in expressed in the endometrium. AQP2 endometrial intracellular calcium required for AQP2 trafficking expression is menstrual cycle-dependent (high at the (Reviews in Jung and Kwon 2016; Ando and Uchida proliferative and midsecretory phases). 2018; De Ieso and Yool 2018; Ranieri et al., 2019). However, cAMP-independent mechanisms for AQP2 trafficking also exist. Nuclear receptors, especially PPARG (Peroxisome proliferator-activated receptor gamma), NR1H2 (LXRB, Liver X receptor beta), NR1H4 (FXR, Farnesoid X receptor), NR3C1 (GR, Glucocorticoid receptor), NR3C2 (MR, Mineralocorticoid receptor) and ESR1 (Estrogen receptor alpha) regulate AQP2 abundance and membrane translocation. PPARG induces increased AQP2 expression, sodium and Figure 3. ModBase predicted comparative 3D structure. water retention and edema. NR3C1 and NR1H4 also Localisation activate AQP2 expression. NR3C2 and NR1H2 AQP2 undergoes a constitutive recycling: its reduce AQP2 expression. ESR1 mediates the trafficking from intracellular vesicles into the plasma inhibitory effect of estradiol on AQP2 expression membrane and endocytic retrieval to its intracellular (Zhang et al., 2016). storage site. AQP2 forms homotetramers in the Other factors capable of regulating AQP2: endoplasmic reticulum, passes through the Golgi extracellular osmotic pressure, insulin (INS), nuclear apparatus and is stored in intracellular vesicles in the factor kB (NFkB), renin/angiotensin/aldosterone perinuclear region. Under resting conditions, AQP2 system, kinins, nitric oxide, adenosine, ATP and binds monomeric G-actin (ACTG1). F-actin endothelins. PTGER2 (Prostaglandin E receptor 2) destabilization facilitates translocation of AQP2 to also controls AQP2 expression. The phosphorylated the apical plasma membrane and water reabsorption activation of CREBBP upregulates AQP2 gene (Vukićević et al., 2016). transcription (reviewed in Zhang et al., 2016). Actin-polymerization/depolymerization Function Actin-depolymerization promotes AQP2 trafficking AQPs main's role is to maintain tissue water balance. to the plasma membrane. TPM3 and MSN AQPs also facilitate cell migration, cell proliferation (Tropomyosin 3 and Moesin) result in F-actin and cell adhesion. Cell migration: AQPs concentrate destabilization. MLCK (Myosin light chain kinase) at the leading end of migrating cells and facilitate the also facilitates AQP2 trafficking to the plasma formation of the lamellipodium (Papadopoulos and membrane by regulating actin filament organization. Saadoun, 2015). Cell proliferation: AQPs may RHOA stimulates actin polymerization, which activate transduction pathways such as the mitogen- inhibits AQP2 trafficking to the plasma membrane. activated protein kinase pathways or the Wnt/beta- Transcription catenin (CTNNB1) signaling. FOSB (FosB proto-oncogene, AP-1 transcription AQP2 key physiological role is water reabsorption factor subunit), CREBBP, calcineurins (protein in collecting duct of the kidney to concentrate urine. phosphatase 3 subunits) MAPK3 / MAPK1 (so Vasopressin / vasopressin receptor / aquaporin-2 called "ERK1/ERK2") and NFAT5 (nuclear factor axis of activated T cells 5) increase AQP2 transcription, In the kidney, AVP 46535 (vasopressin) binds to while NFkB reduces AQP2 gene transcription. AVPR2 732 (type 2 vasopressin receptor (V2R)) Endocytosis/ubiquitination/degradation located in the basolateral membrane of the principal FOSB/ TFAP2A (transcription factor AP-2 alpha cells of the collecting ducts and increases osmotic (activating enhancer binding protein 2 alpha)) water transport through the regulation of the (AP1/AP2) mediates clathrin-mediated endocytosis aquaporin-2 water channel localized in the kidney of AQP2. connecting tubules and collecting ducts. Upon
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VTA1 (vesicle trafficking 1) facilitates AQP2 Glioma lysosomal degradation. MAPK14 (p38-MAPK) The expression of both ESR2 (Estrogen Receptor 2 phosphorylates AQP2 to induce ubiquitination and (ER beta)) and AQP2 was low in glioma cells from proteasomal degradation of AQP2. Protein kinases C patient tissues and glioblastoma cell lines. induce ubiquitination, endocytosis and degradation AQP2 promoted the transcriptional activity of LAX1 of AQP2 (Review in Vukićević et (Lymphocyte transmembrane adaptor 1) and al., 2016). inhibited cell invasion. ESR2 may function as AQP2 promoter in the Mutations nucleus to sustain cells stability while ESRRA Germinal (Estrogen-related receptor alpha) would acts as an antagonist of AQP2 (Wan et al. 2018). AQP2 is responsible for nephrogenic non-X-linked diabetes insipidus, a disease characterized by the Kidney adenocarcinomay kidney's inability to concentrate urine (see below). A t(3;12)(p13;q13) AQP2/ FOXP1 has been found in adenocarcinoma of the kidney (Hu et al., 2018). Implicated in To be noted Dysregulation and dysfunction of AQP2 cause many disorders related to water balance in humans and Aquaporin-targeted drugs: Heavy metal ions animals, including polyuria and dilutional (mercury, silver, gold) are inhibitors of aquaporin-1. hyponatremia (Zan et al., 2016). The Henle loop diuretic bumetanide and analogues Nephrogenic diabetes insipidus. AqB013 and AqF026 also inhibit aquaporin-1. The quaternary ammonium compound Nephrogenic diabetes insipidus is characterized by tetraethylammonium is an inhibitor of aquaporin-1 the kidney's inability to concentrate urine even with water permeability (Verkman et al., 2014; Tomita et normal or elevated concentration of vasopressin. al., 2017). Polyuria/polydipsia and electrolyte imbalance is present from birth. References The antidiuretic peptide hormone arginine- vasopressin (AVP) is synthesized in the Ando F, Uchida S. Activation of AQP2 water channels hypothalamus. Vasopressin binds its receptor without vasopressin: therapeutic strategies for congenital nephrogenic diabetes insipidus. Clin Exp Nephrol. 2018 AVPR2 (arginine vasopressin receptor 2) in the Jun;22(3):501-507 basolateral membrane of cells of the renal collecting De Ieso ML, Yool AJ. Mechanisms of Aquaporin-Facilitated ducts, inducing the vasopressin / vasopressin Cancer Invasion and Metastasis. Front Chem. 2018;6:135 receptor / aquaporin-2 axis. Nephrogenic diabetes insipidus occurs either when: Hu X, Wang Q, Tang M, Barthel F, Amin S, Yoshihara K, Lang FM, Martinez-Ledesma E, Lee SH, Zheng S, Verhaak AVPR2 is mutated (90% of cases, "X-linked RGW. TumorFusions: an integrative resource for cancer- nephrogenic diabetes insipidus": AVPR2 locates in associated transcript fusions. Nucleic Acids Res. 2018 Jan Xq28), or when 4;46(D1):D1144-D1149 AQP2 is mutated (10% of cases, "nephrogenic non- Huber VJ, Tsujita M, Nakada T. Aquaporins in drug X-linked diabetes insipidus"; both dominant and discovery and pharmacotherapy Mol Aspects Med 2012 autosomal recessive forms have been reported. Oct-Dec;33(5-6):691-703 Patients with recessive forms are either Jung HJ, Kwon TH. Molecular mechanisms regulating homozygous, or compound heterozygous). aquaporin-2 in kidney collecting duct Am J Physiol Renal Nephrogenic diabetes insipidus can also be induce Physiol 2016 Dec 1;311(6):F1318-F1328 by lithium, demethylchlortetracycline or other drugs Papadopoulos MC, Saadoun S. Key roles of aquaporins in (Ranieri et al., 2019). tumor biology Biochim Biophys Acta 2015 Oct;1848(10 Pt B):2576-83 Uterus endometrial carcinoma Ranieri M, Di Mise A, Tamma G, Valenti G. Vasopressin- There was an increased expression level of AQP2 in aquaporin-2 pathway: recent advances in understanding endometrial carcinoma, in relation to estradiol level. water balance disorders F1000Res 2019 Feb 4;8 AQP2 was mainly located in glandular epithelial Verkman AS, Anderson MO, Papadopoulos MC. cells. An estrogen response element was found in the Aquaporins: important but elusive drug targets Nat Rev promoter of AQP2. In AQP2 knockdown Drug Discov 2014 Apr;13(4):259-77 endometrial carcinoma cells, there was an alteration Vukićević T, Schulz M, Faust D, Klussmann of the cell morphology by decreasing the expression E. The Trafficking of the Water Channel Aquaporin-2 in of ANXA2 (Annexin A2) and F-actin (Zou et al., Renal Principal Cells-a Potential Target for Pharmacological Intervention in Cardiovascular Diseases 2011). Front Pharmacol 2016 Feb 11;7:23
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Wan S, Jiang J, Zheng C, Wang N, Zhai X, Fei X, Wu R, Zou LB, Zhang RJ, Tan YJ, Ding GL, Shi S, Zhang D, He Jiang X. Estrogen nuclear receptors affect cell migration by RH, Liu AX, Wang TT, Leung PC, Sheng JZ, Huang HF. altering sublocalization of AQP2 in glioma cell lines Cell Identification of estrogen response element in the Death Discov 2018 Oct 17;4:49 aquaporin-2 gene that mediates estrogen-induced cell migration and invasion in human endometrial carcinoma J Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna Clin Endocrinol Metab 2011 Sep;96(9):E1399-408 R, Kim H, Verhaak RG. The landscape and therapeutic relevance of cancer-associated transcript fusions This article should be referenced as such: Oncogene 2015 Sep 10;34(37):4845-54 Huret JL. AQP2 (aquaporin 2). Atlas Genet Cytogenet Zhang XY, Wang B, Guan YF. Nuclear Receptor Regulation Oncol Haematol. 2020; 24(1):28-32. of Aquaporin-2 in the Kidney Int J Mol Sci 2016 Jul 11;17(7)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 32 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Review
BUB3 (BUB3 mitotic checkpoint protein) Jorge Antonio Elias Godoy Carlos, João Agostinho Machado-Neto Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil; [email protected]; [email protected] Published in Atlas Database: March 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/BUB3ID855ch10q26.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70647/03-2019-BUB3ID855ch10q26.pdf DOI: 10.4267/2042/70647 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract DNA/RNA BUB3 is a WD40 protein that belongs to spindle Description mitotic checkpoint complex, which monitors the The entire BUB3 gene is approximately 16.2 Kb chromosome attachment to mitotic (or meiotic) fuse (start: 123154277 and end: 123170467 bp; and prevents premature chromosome segregation. orientation: Forward strand). Alterations in BUB3 have been associated with chromosomal instability and aneuploidy, but their Transcription contribution for cancer development and progression are poorly understood, and appear to differ The BUB3 gene encodes for 4 transcript variants: depending on the type of cancer. there are two transcript variants deposited in the The present review contains data on BUB3 DNA, NCBI database RNA, protein encoded and function. (https://www.ncbi.nlm.nih.gov/gene) and two additional transcript variants reported in Ensembl Keywords (http://www.ensembl.org/). BUB3; Mitotic checkpoint protein BUB3; WD40 The transcript variant 1 is the longest transcript protein; Spindle checkpoint; Cell cycle; Anaphase- variant (exons: 8, coding exons: 7, transcript length: promoting complex. 7828 bp) and encodes the isoform a (328 amino acids [aa]). The transcript variant 2 present an alternative Identity splice site in 3' coding region (exons: 8, coding Other names: BUB3L, hBUB3 exons: 7, transcript length: 1361 bp), which leads to a frameshift and a shorter and distinct C-terminus HGNC (Hugo): BUB3 compared to isoform a (isoform b, 326 aa).. Location: 10q26.13
Figure 1. BUB3 protein structure. BUB3 protein presents seven WD40 repeat domain, a nearly 40 amino acids (aa) motif rich in tryptophan-aspartic acids (W-D). The position of aa are indicated.
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 33 BUB3 (BUB3 mitotic checkpoint protein) Elias Godoy Carlos JA, Machado-Neto J
Figure 2. BUB3, a component of mitotic checkpoint complex (MCC). (Upper panel) The presence of unattached kinotochores induces the formation of MCC composed by BUB3, BUBR1, MAD2L1, which sequester CDC20, leads the anaphase-promoting complex/cyclosome (APC/C) inhibition and cell cycle arrest. (Lower panel) In the presence of attached kinotochores, the MCC complex is disassembled and the CDC20 is released, which leads to APC/C activation (which in turn triggers degradation of securin and cyclin B), chromosomal segregation and completion of mitosis.
The transcript variant 3 present 6 coding exons, a complex (Sudakin et al., 2001). In interphase cells, transcript length of 895 bp and a translation length BUB3 is localized in cytosol (Yoon et al., 2004). of 278 aa Function The transcript variant 4 is shorter transcript presenting 5 exons (being 4 coding exons), a BUB3 protein is a component of the mitotic transcript length 667 bp and resulting protein of 145 checkpoint complex (MCC), which present a crucial aa. activity monitoring the state of chromosome attachment to the mitotic (or meiotic) fuse and Protein prevents loss of sister chromatid cohesion and premature chromosome segregation in the presence Description of unattached or incorrectly attached chromosomes BUB3 is a WD40 protein that create a symmetric to the spindle by inhibition of the anaphase- circular wall around a central pore or funnel region promoting complex/cyclosome (APC/C) (Lopes et with its seven-blade β-propeller structure, acting as al., 2005; Musacchio, 2015). The canonical BUB3- a scaffolding protein for its binding partners BUB1B related cellular signaling is illustrated in Figure 2. (BUBR1) and BUB1 (Prinz et al., 2016; Seeley et al., Using a Drosophila melanogaster model, Morais da 1999). Silva and colleagues (Morais da Silva et al., 2013) The primary structure of BUB3 is illustrated in reported that BUB3 inhibition resulted in increased Figure 1. proliferative potential, promoted tumorigenesis and widespread chromosomal aneuploidy. Interesting, Expression loss of cytoplasmatic, but not attached-kinetochore, Ubiquitous. BUB3 pool was found to be driven tumorigenesis, indicating a novel non-kinetochore-dependent tumor Localisation suppressing function for BUB3 (Morais da Silva et BUB3 is localized preferentially in unattached al., 2013). Additional non-canonical functions of kinetochores during mitosis (especially BUB3 had been described during interphase. BUB3 prometaphase), participating of mitotic checkpoint and CDC20 form a complex with histone
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BUB3 (BUB3 mitotic checkpoint protein) Elias Godoy Carlos JA, Machado-Neto J
deacetylases, which seems to confer transcriptional repressor activity (Yoon et al., 2004). Wan and Implicated in colleagues (Wan et al., 2015) reported that BUB3 Adrenocortical carcinoma regulates RNA splicing, R-loop formation, DNA damage, and TP53 activation. In a cohort of 79 adrenocortical carcinoma patients, increased levels of BUB3 mRNA levels was Homology associated with high grade tumors and poor clinical The BUB3 gene and protein is highly homologous outcomes (Subramanian and Cohen, 2019). In among different species, as shown in Table 1. addition, Oncomine Giordano ACC data analysis revealed increased levels of BUB3 in adrenocortical % Identity for: carcinoma compared to normal adrenal samples Symbol Protein DNA Homo sapiens BUB3 (Subramanian and Cohen, 2019). vs. P.troglodytes BUB3 100.0 99.8 Breast cancer vs. M.mulatta BUB3 100.0 98.8 BUB3 promoter polymorphisms (rs3763740, vs. B.taurus BUB3 100.0 93.5 rs3763741, rs17014712, rs3808960 and rs3808961) vs. M.musculus Bub3 100.0 90.4 did not impact familial breast cancer risk in a vs. R.norvegicus Bub3 100.0 91.1 German cohort of 441 breast cancer patients and 552 controls matched by age, ethnicity and geographical vs. G.gallus BUB3 96.9 84.0 region (Vaclavicek et al., 2007). Similarly, the vs. X.tropicalis bub3 93.2 79.5 polymorphisms rs11248416, rs11248419, and vs. D.rerio bub3 86.2 73.7 rs6599657 in BUB3 gene were not associated with vs. D.melanogaster Bub3 61.1 59.9 risk of breast cancer development in a Chinese vs. A.gambiae AgaP_AGAP010544 62.0 59.2 cohort of 462 breast cancer patients and 529 controls (Wang et al., 2014). vs. S.pombe bub3 38.0 45.0 BUB3 was highly expressed in primary and cell lines vs. A.thaliana BUB3.1 55.1 55.0 from breast cancer compared to immortalized breast vs. A.thaliana BUB3.2 56.3 55.8 cancer epithelium or normal primary mammary cells vs. O.sativa Os03g0448600 56.3 57.4 (Yuan et al., 2006). BUB3 gene region (10q26.3) Table 1. Comparative identity of human BUB3 with other was found to be amplified and overexpressed in species. (Source: http://www.ncbi.nlm.nih.gov/homologene) breast cancer samples (Turner et al., 2010). BUB3 mRNA levels were upregulated in doxorubicin and Mutations cyclophosphamide sensitive breast cancer tumors (Cleator et al., 2006). In MDA-MB-231 breast Somatic cancer cells, BUB3 expression was induced by BMP Recurrent mutations in the BUB3 gene are rare. A signaling (Yan et al., 2012). total of 81 unique samples presented BUB3 Cervical cancer mutations, which are distributed on 75 different mutations (60 missense substitutions, 10 Using proteomics approach, BUB3 was found to be synonymous substitutions, 1 nonsense substitutions, downregulated by paclitaxel and 5-fluorouracil in 2 inframe deletions and 2 frameshift deletions), were HeLa cells (Lee et al., 2005; Yim et al., 2004). In found among the 47120 unique samples reported in addition, BUB3 inhibition by siRNA reduced COSMIC (Catalogue of Somatic Mutations in paclitaxel-induced cell cycle arrest (Lee et al., 2005). Cancer; Chronic myeloid leukemia http://cancer.sanger.ac.uk/cancergenome/projects/c BCR/ ABL1 expression repressed spindle osmic). In agreement, 0.2% of 74247 tested samples checkpoint components, including BUB3, to escape presented BUB3 somatic mutation as reported in from metaphase arrest (Wolanin et al., 2010). cBioPortal (http://www.cbioportal.org), which correspond to 154 mutations: 132 missense Colorectal cancer substitutions, 17 truncating and 5 inframe mutations. Three missense variants in BUB3 [predicted to be Of note, there are 55 duplicate mutations in patients pathogenic: c.790T>C (p.F264L), c.63G>C with multiple samples. A total of 472 (0.8 %) (p.K21N) and c.446G>A (p.R149Q)] were observed samples presented any type of genetic alteration in in familial or early onset colorectal cancer patients BUB3, when mutations, amplifications, deep (n=185), which were not found in large cohort of deletions and multiple alterations were considered in control (n=1154) (de Voer et al., 2013). In 55817 cancer samples. These findings corroborate agreement, Mur and colleagues (Mur et al., 2018) initial studies in different types of cancer (Hernando reported that BUB3 was found to be mutated [BUB3 et al., 2001). c.77C>T (p.T26I)] in familial colorectal cancer.
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BUB3 (BUB3 mitotic checkpoint protein) Elias Godoy Carlos JA, Machado-Neto J
Gastric cancer Ovarian cystadenoma High BUB3 gene expression was observed in 34 out In ML10 cells, a human ovarian cystadenoma model, of 43 gastric cancer tumors samples compared with BUB3 nuclear expression and phosphorylation were their matched normal mucosa counterpart, which increased in low compared to high replicative age was associated with Ki-67 expression, but not with cells, which may be involved in prolonged mitotic aneuploidy (Grabsch et al., 2003). The BUB3 arrest and cytokinesis failure observed in this polymorphism, rs7897156, did not impact gastric cellular model (Austria et al., 2018). cancer susceptibility in a study including 164 gastric Pancreatic cancer cancer patients and 381 ethnicity matched controls (Mesic et al., 2017). A mutation in BUB3 (c.576+1G>A) was found among deleterious germline mutations (n=33) in Glioblastoma sporadic pancreatic adenocarcinoma patients he genetic variation C>T in the position -6 of the (n=854) (Shindo et al., 2017). In pancreatic cells, BUB3 gene, but not in coding sequence, was DMAP1/BUB3 complex repressed antiapoptotic detected in 4 out of 22 glioblastoma samples (Reis et genes transcription mediating mitotic stress-induced al., 2001). Bie and colleagues (Bie et al., 2011) apoptosis and improved in vivo paclitaxel-induced reported that BUB3 was highly expressed in grade tumor growth inhibition, which are impaired by SRC III and IV gliomas compared to normal brain activity (Li et al., 2018). samples. On the other hand, Morales and colleagues Renal cell carcinoma (Morales et al., 2013) reported a downregulation of BUB3 in primary samples and cell lines derived BUB3 gene expression profile was similar between from glioblastoma compared to non-neoplastic white samples from papillary renal cell carcinoma, matter from epileptic patients. chromophobe renal cell carcinoma and clear cell In BUB3-depleted U87MG glioblastoma cells, the renal cell carcinoma patients and normal kidney expression o BUB3Y207F, which mimics an tissues (Pinto et al., 2007; Pinto et al., 2008). unphosphorylated form, strongly reduced tumor growth and improved survival compared to the To be noted WT expression BUB3 in intracranial tumor mice BUB3 knockout mice presented accumulation of model, indicating that BUB3 phosphorylation at mitotic errors during embryogenesis and were Y207 site is required for tumorigenesis (Jiang et al., unviable after day 6.5-7.5 postcoitus (Kalitsis et al., 2014). 2000). BUB3 haploinsufficiency leaded to Lung cancer chromosome instability and predisposition to Initial observations did not identify genetic defects carcinogen-induced, but not to spontaneous, tumors in BUB3 gene in lung cancer patients (Haruki et al., development in mice (Babu et al., 2003; Kalitsis et 2001). In cohort of 766 non-small cell lung cancer al., 2005; Rao et al., 2009). Induced-BUB3 patients, the presence of allele T of polymorphism in mutations presented no effect on the genome BUB3 (rs7897156C>T) was associated with poor rearrangements rate in Saccharomyces cerevisiae overall survival (Kang et al., 2017). Using H1299 (Myung et al., 2001). In healthy humans, BUB3 and A549 non-small cell lung cell lines, functional genetic variations were not associated with non- studies based in luciferase assays indicated that T specific chromosomal aberrations (Forsti et al., allele induced enhancement of BUB3 expression. In 2016). addition, increased BUB3 expression was observed in lung tumor tissues compared to non-malignant References lung tissues (Kang et al., 2017). Austria T, Marion C, Yu V, Widschwendter M, Hinton DR, Dubeau L. Mechanism of cytokinesis failure in ovarian Osteosarcoma cystadenomas with defective BRCA1 and P53 pathways. Int Loss of heterozygosity at 10q26, but not BUB3 J Cancer. 2018 Dec 1;143(11):2932-2942 mutations, was found in ostesarcoma samples Babu JR, Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, (Mendoza et al., 2005). In Saos-2 osteosarcoma van Deursen JM. Rae1 is an essential mitotic checkpoint cells, TAp73α (an isoform of TP73) binds to BUB3 regulator that cooperates with Bub3 to prevent chromosome and BUB1, which leads to potential alteration of missegregation. J Cell Biol. 2003 Feb 3;160(3):341-53 mitotic checkpoint function of these proteins and Bie L, Zhao G, Cheng P, Rondeau G, Porwollik S, Ju Y, Xia aneuploidy (Vernole et al., 2009). In U2OS XQ, McClelland M. The accuracy of survival time prediction for patients with glioma is improved by measuring mitotic osteosarcoma cells, but not normal fibroblast, BUB3 spindle checkpoint gene expression. PLoS One. silencing reduces cell proliferation and 2011;6(10):e25631 clonogenicity and induces DNA fragmentation Cleator S, Tsimelzon A, Ashworth A, Dowsett M, Dexter T, (Prinz et al., 2016). Powles T, Hilsenbeck S, Wong H, Osborne CK, O'Connell P, Chang JC. Gene expression patterns for doxorubicin
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BUB3 (BUB3 mitotic checkpoint protein) Elias Godoy Carlos JA, Machado-Neto J
(Adriamycin) and cyclophosphamide (cytoxan) (AC) de Oliveira HF, Scrideli CA, Tone LG. BUB1 and BUBR1 response and resistance. Breast Cancer Res Treat. 2006 inhibition decreases proliferation and colony formation, and Feb;95(3):229-33 enhances radiation sensitivity in pediatric glioblastoma cells Childs Nerv Syst 2013 Dec;29(12):2241-8 Försti A, Frank C, Smolkova B, Kazimirova A, Barancokova M, Vymetalkova V, Kroupa M, Naccarati A, Vodickova L, Mur P, De Voer RM, Olivera-Salguero R, Rodríguez- Buchancova J, Dusinska M, Musak L, Vodicka P, Hemminki Perales S, Pons T, Setién F, Aiza G, Valdés-Mas R, Bertini K. Genetic variation in the major mitotic checkpoint genes A, Pineda M, Vreede L, Navarro M, Iglesias S, González S, associated with chromosomal aberrations in healthy Brunet J, Valencia A, Esteller M, Lázaro C, Kops GJPL, humans. Cancer Lett. 2016 Oct 1;380(2):442-6 Urioste M, Puente XS, Capellá G, Valle L. Germline mutations in the spindle assembly checkpoint genes BUB1 Grabsch H, Takeno S, Parsons WJ, Pomjanski N, Boecking and BUB3 are infrequent in familial colorectal cancer and A, Gabbert HE, Mueller W. Overexpression of the mitotic polyposis Mol Cancer 2018 Feb 15;17(1):23 checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer--association with tumour cell proliferation. J Pathol. Musacchio A. The Molecular Biology of Spindle Assembly 2003 May;200(1):16-22 Checkpoint Signaling Dynamics Curr Biol 2015 Oct 19;25(20):R1002-18 Haruki N, Saito H, Harano T, Nomoto S, Takahashi T, Osada H, Fujii Y, Takahashi T. Molecular analysis of the Myung K, Datta A, Kolodner RD. Suppression of mitotic checkpoint genes BUB1, BUBR1 and BUB3 in spontaneous chromosomal rearrangements by S phase human lung cancers. Cancer Lett. 2001 Jan 26;162(2):201- checkpoint functions in Saccharomyces cerevisiae Cell 5 2001 Feb 9;104(3):397-408 Hernando E, Orlow I, Liberal V, Nohales G, Benezra R, Pinto M, Soares MJ, Cerveira N, Henrique R, Ribeiro FR, Cordon-Cardo C. Molecular analyses of the mitotic Oliveira J, Jerónimo C, Teixeira MR. Expression changes of checkpoint components hsMAD2, hBUB1 and hBUB3 in the MAD mitotic checkpoint gene family in renal cell human cancer. Int J Cancer. 2001 Jul 20;95(4):223-7 carcinomas characterized by numerical chromosome changes Virchows Arch 2007 Apr;450(4):379-85 Jiang Y, Li X, Yang W, Hawke DH, Zheng Y, Xia Y, Aldape K, Wei C, Guo F, Chen Y, Lu Z. PKM2 regulates Pinto M, Vieira J, Ribeiro FR, Soares MJ, Henrique R, chromosome segregation and mitosis progression of tumor Oliveira J, Jerónimo C, Teixeira MR. Overexpression of the cells. Mol Cell. 2014 Jan 9;53(1):75-87 mitotic checkpoint genes BUB1 and BUBR1 is associated with genomic complexity in clear cell kidney carcinomas Cell Kalitsis P, Fowler KJ, Griffiths B, Earle E, Chow CW, Oncol 2008;30(5):389-95 Jamsen K, Choo KH. Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 mice. Prinz F, Puetter V, Holton SJ, Andres D, Stegmann CM, Genes Chromosomes Cancer. 2005 Sep;44(1):29-36 Kwiatkowski D, Prechtl S, Petersen K, Beckmann G, Kreft B, Mumberg D, Fernández-Montalván A. Functional and Kang HG, Yoo SS, Choi JE, Hong MJ, Do SK, Jin CC, Kim Structural Characterization of Bub3·BubR1 Interactions S, Lee WK, Choi SH, Lee SY, Kim HJ, Lee SY, Lee J, Cha Required for Spindle Assembly Checkpoint Signaling in SI, Kim CH, Seok Y, Lee E, Cho S, Jheon S, Park JY. Human Cells J Biol Chem 2016 May 20;291(21):11252-67 Polymorphisms in mitotic checkpoint-related genes can influence survival outcomes of early-stage non-small cell Rao CV, Yamada HY, Yao Y, Dai W. Enhanced genomic lung cancer. Oncotarget. 2017 Sep 22;8(37):61777-61785 instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic Lee KH, Yim EK, Kim CJ, Namkoong SE, Um SJ, Park JS. studies in mice Carcinogenesis 2009 Sep;30(9):1469-74 Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Reis RM, Nakamura M, Masuoka J, Watanabe T, Colella S, Jul;98(1):45-53 Yonekawa Y, Kleihues P, Ohgaki H. Mutation analysis of hBUB1, hBUBR1 and hBUB3 genes in glioblastomas Acta Li J, Hu B, Wang T, Huang W, Ma C, Zhao Q, Zhuo L, Zhang Neuropathol 2001 Apr;101(4):297-304 T, Jiang Y. C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in Seeley TW, Wang L, Zhen JY. Phosphorylation of human pancreatic cancer. Mol Cancer. 2018 Dec 15;17(1):174 MAD1 by the BUB1 kinase in vitro Biochem Biophys Res Commun 1999 Apr 13;257(2):589-95 Lopes CS, Sampaio P, Williams B, Goldberg M, Sunkel CE. The Drosophila Bub3 protein is required for the mitotic Shindo K, Yu J, Suenaga M, Fesharakizadeh S, Cho C, checkpoint and for normal accumulation of cyclins during Macgregor-Das A, Siddiqui A, Witmer PD, Tamura K, Song G2 and early stages of mitosis. J Cell Sci. 2005 Jan TJ, Navarro Almario JA, Brant A, Borges M, Ford M, Barkley 1;118(Pt 1):187-98 T, He J, Weiss MJ, Wolfgang CL, Roberts NJ, Hruban RH, Klein AP, Goggins M. Deleterious Germline Mutations in Mendoza S, David H, Gaylord GM, Miller CW. Allelic loss at Patients With Apparently Sporadic Pancreatic 10q26 in osteosarcoma in the region of the BUB3 and Adenocarcinoma J Clin Oncol 2017 Oct 20;35(30):3382- FGFR2 genes. Cancer Genet Cytogenet. 2005 Apr 3390 15;158(2):142-7 Subramanian C, Cohen MS. Over expression of DNA Mesic A, Markocic E, Rogar M, Juvan R, Hudler P, Komel damage and cell cycle dependent proteins are associated R. Single nucleotide polymorphisms rs911160 in AURKA with poor survival in patients with adrenocortical carcinoma and rs2289590 in AURKB mitotic checkpoint genes contribute to gastric cancer susceptibility. Environ Mol Surgery 2019 Jan;165(1):202-210 Mutagen. 2017 Dec;58(9):701-711 Sudakin V, Chan GK, Yen TJ. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, Morais da Silva S, Moutinho-Santos T, Sunkel CE. A tumor BUB3, CDC20, and MAD2 J Cell Biol 2001 Sep suppressor role of the Bub3 spindle checkpoint protein after 3;154(5):925-36 apoptosis inhibition J Cell Biol 2013 Apr 29;201(3):385-93 Turner N, Lambros MB, Horlings HM, Pearson A, Sharpe R, Morales AG, Pezuk JA, Brassesco MS, de Oliveira JC, de Natrajan R, Geyer FC, van Kouwenhove M, Kreike B, Paula Queiroz RG, Machado HR, Carlotti CG Jr, Neder L,
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Mackay A, Ashworth A, van de Vijver MJ, Reis-Filho JS. levels in human breast cancer cells Cell Signal 2012 Integrative molecular profiling of triple negative breast Apr;24(4):961-8 cancers identifies amplicon drivers and potential therapeutic targets Oncogene 2010 Apr 8;29(14):2013-23 Yim EK, Lee KH, Bae JS, Namkoong SE, Um SJ, Park JS. Proteomic analysis of antiproliferative effects by treatment Vaclavicek A, Bermejo JL, Wappenschmidt B, Meindl A, of 5-fluorouracil in cervical cancer cells DNA Cell Biol 2004 Sutter C, Schmutzler RK, Kiechle M, Bugert P, Burwinkel Nov;23(11):769-76 B, Bartram CR, Hemminki K, Försti A. Genetic variation in the major mitotic checkpoint genes does not affect familial Yoon YM, Baek KH, Jeong SJ, Shin HJ, Ha GH, Jeon AH, breast cancer risk Breast Cancer Res Treat 2007 Hwang SG, Chun JS, Lee CW. WD repeat-containing Dec;106(2):205-13 mitotic checkpoint proteins act as transcriptional repressors during interphase FEBS Lett 2004 Sep 24;575(1-3):23-9 Vernole P, Neale MH, Barcaroli D, Munarriz E, Knight RA, Tomasini R, Mak TW, Melino G, De Laurenzi V. TAp73alpha Yuan B, Xu Y, Woo JH, Wang Y, Bae YK, Yoon DS, Wersto binds the kinetochore proteins Bub1 and Bub3 resulting in RP, Tully E, Wilsbach K, Gabrielson E. Increased polyploidy Cell Cycle 2009 Feb 1;8(3):421-9 expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability Clin Cancer Res 2006 Wan Y, Zheng X, Chen H, Guo Y, Jiang H, He X, Zhu X, Jan 15;12(2):405-10 Zheng Y. Splicing function of mitotic regulators links R-loop- mediated DNA damage to tumor cell killing J Cell Biol 2015 de Voer RM, Geurts van Kessel A, Weren RD, Ligtenberg Apr 27;209(2):235-46 MJ, Smeets D, Fu L, Vreede L, Kamping EJ, Verwiel ET, Hahn MM, Ariaans M, Spruijt L, van Essen T, Houge G, Wang P, Wang Y, Yan H, Xie Q, Zhao L, Xu S, Zhao Q. Schackert HK, Sheng JQ, Venselaar H, van Ravenswaaij- Genetic variation in the major mitotic checkpoint genes and Arts CM, van Krieken JH, Hoogerbrugge N, Kuiper RP. risk of breast cancer: a multigenic study on cancer Germline mutations in the spindle assembly checkpoint susceptibility Tumour Biol 2014 Jul;35(7):6701-5 genes BUB1 and BUB3 are risk factors for colorectal cancer Gastroenterology 2013 Sep;145(3):544-7 Wolanin K, Magalska A, Kusio-Kobialka M, Podszywalow- Bartnicka P, Vejda S, McKenna SL, Mosieniak G, Sikora E, This article should be referenced as such: Piwocka K. Expression of oncogenic kinase Bcr-Abl impairs mitotic checkpoint and promotes aberrant divisions and Elias Godoy Carlos JA, Machado-Neto J. BUB3 (BUB3 resistance to microtubule-targeting agents Mol Cancer Ther mitotic checkpoint protein). Atlas Genet Cytogenet Oncol 2010 May;9(5):1328-38 Haematol. 2020; 24(1):33-38. Yan H, Zhu S, Song C, Liu N, Kang J. Bone morphogenetic protein (BMP) signaling regulates mitotic checkpoint protein
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 38 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Review
SLC6A4 (solute carrier family 6 member 4) Rafig Gurbanov, Berkay Kalkanci Department of Molecular Biology and Genetics (RG); Bilecik Seyh Edebali University, Department of Biotechnology (BK), Bilecik Seyh Edebali University, Biotechnology Application and Research Center, Bilecik, Turkey; [email protected]; [email protected]
Published in Atlas Database: March 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC6A4ID49951ch17q11.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70648/03-2019-SLC6A4ID49951ch17q11.pdf DOI: 10.4267/2042/70648 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
behaviour in Alzheimer patients, Seasonal affective Abstract disorder, Major depressive Disorder and Obsessive- The SLC6A4 gene encodes a sodium-dependent compulsive disorder. serotonin reuptake protein delivering the Keywords neurotransmitter serotonin from the synaptic cleft Solute Carrier Family 6 Member 4 (SLC6A4), back to the presynaptic end. Its main function is to Serotonin (5-HT), Serotonin transporter protein (5- abort the activity of serotonin and forward it to HTT), Anxiety, Alcoholism, Hypertension, Mental neurotransmitter pool for recycling. The Disorders. psychomotor stimulant drugs mainly amphetamines and cocaine act on this transmembrane protein which Identity is a member of the sodium: neurotransmitter Other names: 5-HTT, 5-HTTLPR, 5HTT, HTT, symporter family. SLC6A4 gene polymorphisms OCD1, SERT, SERT1, hSERT affect the rate of serotonin reuptake and play an important role in pathogenesis of various illnesses HGNC (Hugo): SLC6A4 like Sudden infant death syndrome, aggressive Location: 17q11.2
Figure 1. Genomic location of SLC6A4 (Chromosome 17 - NC_000017.11 Reference GRCh38.p12 Primary Assembly)
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 39 SLC6A4 (solute carrier family 6 member 4) Gurbanov R, Kalkanci B
Figure 2. Chromosomal Location of SLC6A4. Cytogenetic Location: 17q11.2, which is the long (q) arm of chromosome 17 at position 11.2 (U.S. National Library of Medicine)
Figure 3. Numbers and illustrative sizes of exons of human SLC6A4. (https:\\www.atlasgeneticsoncology.org)
is N-X-S/T (the amide nitrogen glycan binding DNA/RNA region in the asparagine side chain and X is any The SLC6A4 gene is 41,684 bp long (according to amino acid except proline) (Mitra et al., 2006). UCSC, GRCh38/hg38), located on the plus strand The EL2 of the 5-HTT protein has two glycosylation and spans 15 exons (NCBI Homo sapiens sites carrying glycan (Tate and Blakely,. 1994). Annotation Release 109). Mutations in the glycosylation sites of 5-HTT and other NSS proteins generally cause problems in the Transcription transport of neurotransmitter proteins such as The gene has 5 transcripts (Table 1) serotonin at the cell surface (Tate Protein and Blakely,.1994 ; Olivares et al., 1995; Melikian Name Transcript ID bp Biotype (aa) et al., 1996; Li et al., 2004). SLC6A4- Protein ENST00000261707.7 6604 630 aa 201 coding SLC6A4- Protein ENST00000394821.2 2160 618 aa 202 coding SLC6A4- Protein ENST00000401766.6 6543 630 aa 203 coding SLC6A4- No Retained ENST00000578609.1 566 204 protein intron Nonsense SLC6A4- ENST00000579221.5 1069 72 aa mediated 205 decay Figure 4. Structure of human Solute carrier family 6 Table 1. Transcripts of human SLC6A4 gene (Ensemble, member 4. X-ray structure of the ts3 human serotonin GRCh38.p12). transporter complexed with paroxetine (selective serotonin re-uptake inhibitor) at the central site (PDB ID: 5I6X) Protein (https://www.rcsb.org). SLC6A4 gene encodes a serotonin transporter Expression protein (5-HTT) of 70,320 Dalton and composed of SLC6A4 gene is most commonly expressed in 630 amino acids (Figure 4) (Ramamoorthy et al., gastrointestinal tract, female tissues, and lung. It is 1993). The protein belongs to family of less expressed in muscle, skin, endocrine, male, and neurotransmitter/sodium transporter (NSS). NSS female tissues (http://www.proteinatlas.org). family also includes dopamine, glycine and γ - aminobutyric acid (GABA) transporters (Chen et al., Localisation 2004). The members of this family have 12 SLC6A4 is found in various cellular compartments transmembrane domains and intracellular N and C such as cytosol, endosome, plasma membrane, and terminal regions (Yamashita et al., 2005). The large integral component of plasma membrane, integral extracellular structure (EL) between TM3 and TM4 component of postsynaptic membrane, integral is modified by N-linked glycosylation in all component of presynaptic membrane, eukaryotic NSS proteins and the number of N-linked endomembrane system, neuron projection, and glycosylation sites can vary from carrier to carrier. serotonergic synapse (Müller et al., 2006; Brenner et The consensus sequence for N-linked glycosylation
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SLC6A4 (solute carrier family 6 member 4) Gurbanov R, Kalkanci B
al., 2007; Ahmed et al., 2008; Ahmed et al., 2009; the execution of serotonergic function (Gelernter J. Gaudet et al., 2011). Et al., 1998, Catalano M., 1999). Function The 5-HTT activity is rapidly regulated by a number of G-protein-linked receptors and protein kinase- 5-HTT protein activity relies on the concentrations associated pathways including protein kinase C of intracellular potassium and extracellular sodium (PKC), PRKG1 (protein kinase G, PKG), and p38 and chloride ions. It also depends on the membrane mitogen-activated protein kinase (MAPK). The potential generated by sodium-potassium adenosine PKC-dependent phosphorylation and down- triphosphatase for the activity of the 5-HTT protein. regulation of the 5-HTT protein is sensitive to The 5-HTT protein binds itself to sodium, serotonin extracellular 5-HT and plays a regulatory role in the and chloride ions, respectively. transport of 5-HT (Ramamoorthy et al., 1998; Ramamoorthy et al., 1999; Zhu et al., 2004; Samuvel et al., 2005; Prasad et al., 2005). Mutations Most frequent mutations are located in the 5- HTTLPR of the promoter region of SLC6A4 gene. These mutations lead to the clinical picture of Autism (rs6365, rs28914832, rs140700) (Sutcliffe et al., 2005 ; Landaas et al., 2010 ; Adamsen et al., 2011), Increased rigid-compulsive behaviour in autism (rs28914833, rs28914834) (Sutcliffe et al., 2005; Rao et al., 2017), Obsessive-compulsive disorder (rs25532) (Wendland et al., 2007), Major depressive disorder (rs6354) (Rao et al., 2017), Panic disorder (rs3813034) (Gyawali et al., 2010), Unipolar disorder (Ogilvie et al., 1996), and Pulmonary arterial hypertension (Eddahibi et al., 2003) (Table 2). Implicated in The serotonin carrier protein encoded by SLC6A4 gene is the target of serotonin selective reuptake Figure 5. Expression profile of SLC6A4 in different tissues/organs in human. Data were taken from The Human inhibitors, an important class of antidepressant drugs Protein Atlas (http://www.proteinatlas.org) in December, (Ramoz et al., 2006). Three alleles of 17-bp VNTR 2018. (variable number tandem repeat) were detected in Thus, the membrane potential mediates the release the intron 2 region of the gene, between 9 (Stin2.9), of sodium and chloride molecules pre-bound to the 10 (Stin2.10), and 12 (Stin2.12) copies. Presence of 5-HTT protein and the 5-HTT protein passes into the Stin2.9 allele in humans has been reported to cell. The 5-HTT protein releases serotonin in the cell increase the risk of Major depressive disorder and binds a potassium ion to itself. 5-HTT is (MDD) (Ogilvie et al., 1996). activated by potassium ion and may be out of the The 5-HTTLPR promoter sequence of the gene cell. Serotonin (5-hydroxytryptamine; 5-HT) is an comprises two variant repeat length polymorphisms, important neurotransmitter substance in the central known as the 16-element long (L) and 44-bp short and peripheral nervous system. After release of 5-HT (S) variant with 14 repetitive elements (Esterling et into brain synapses, the Na+ and CI-ions-dependent al., 1998; Sen et al., 2004). The L/L genotype from high-affinity serotonin transporter SLC6A4 (also the 5-HTTLPR promoter variants causes more 5- called 5-hydroxytryptamine transporter, 5-HTT, HTT protein expression than the L/S or S/S variants SERT), which is localized in presynaptic neuronal (Canli and Lesch, 2007). membranes, effectively clears 5-HT from the Analysis of lymphoblastoid cell lines with different synaptic space. Thus, the synaptic activity of 5-HT genotypes revealed that the basal activity of the L is terminated by 5-HTT and reintroduced into the variant of the SLC6A4 gene promoter was two times neurotransmitter pool for re-use. In this way, 5-HTT greater than that of the S variant (Lesch et al., 1996). has an important role in the retrieval of serotonin and
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Figure 6. Serotonergic Synapse Pathway Map. Once released from presynaptic axonal terminals, 5-HT binds to receptors, which have been divided into 7 subfamilies on the basis of conserved structures and signalling mechanisms. These families include the ionotropic 5-HT3 receptors and G-protein-coupled 5-HT receptors, the 5-HT1 (Gi /Go -coupled), 5-HT2 (Gq-coupled), 5-HT4/6/7 (Gs-coupled) and 5-HT5 receptors. Presynaptically localized 5-HT1B receptors are thought to be the autoreceptors that suppress excess 5-HT release. 5-HT's actions are terminated by transporter- mediated reuptake into neurons, leading to catabolism by monoamine oxidase. Data were taken from KEGG: Kyoto Encyclopedia of Genes and Genomes (https://www.genome.jp/kegg/) in February, 2019.
Figure 7. Pairwise alignment of SLC6A4 gene protein sequences (in distance from human) (HomoloGene, NCBI).
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Missense/Nonsense Mutations # Location Mutation Protein Reported Phenotype Reference Parasad et al., 1 Exon 2 c.10A>G p.T4A Enhanced 5-HT transport activity 2005 Sutcliffe et al., 2005 2 Exon2 c.167G>C p.G56A Autism, association with Camarena et al., 2012 Rasmussen et al., 3 chr17:30218213 c.603G>C p.K201N Increased transporter activity 2009 Parasad et al., 4 Exon 4 c.643G>A p.E215K MAPK nonresponsiveness 2005 Parasad et al., 5 Exon 6 c.878C>T p.S293F Enhanced 5-HT transport activity 2005 Parasad et al., 6 Exon 7 c.1016C>T p.P339L Reduced uptake activity 2005 Parasad et al.i 7 Exon 8 c.1084C>A p.L362M Enhanced 5-HT transport activity 2005 Sutcliffe et al., 8 Exon 9 c.1273A>C p.I425L Autism, association with 2005 Ozaki et al., Obsessive-compulsive 2003 9 Exon 9 c.1273A>G p.I425V disorder,susceptibility, association Moya et al., 2013 Increased rigid-compulsive behavior in Sutcliffe et al., 10 Exon 10 c.1393T>C p.F465L autism, association with 2005 Sutcliffe et al., Increased rigid-compulsive behavior in 11 Exon 12 c.1648C>G p.L550V 2005 autism, association with Rao et al., 2017 Parasad et al., 12 Exon13 c.1815A>C p.K605N MAPK nonresponsiveness 2005 Rao et al., 2017 Parasad et al., 13 Exon 14 c.1861C>T p.P621S MAPK nonresponsiveness 2005 Splicing Mutation Sutcliffe et al., 2005 14 chr17:30216371 c.838-155G>A NA Autism, association with Landaas et al., 2010 Regulatory Mutation Hu et al., 2006 Perroud et al., 2010 Obsessive-compulsive disorder, Hung et al., 2011 15 chr17:30237328 c.-1936G>A NA association with Moya et al., 2013 Stacey et al., 2013 Wendland et al., Obsessive-compulsive disorder, 2008 16 chr17:30237152 c.-1760T>C NA association with Fuxman Bass et al., 2015 Major depressive disorder, association 17 chr17:30222880 c.-185A>C NA Rao et al., 2017 with Vallender et al., 18 chr17:30197993 c.463T>G NA Increased expression 2008
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Seneviratne et al., 2009 Gyawali et al., 2010 19 chr17:30197786 c.670T>G Na Panic disorder, association with Aoki et al., 2010 Hartley et al., 2012 Deletion Helis et al., 1996 Marziniak et al., 2005 20 Promoter c.1212-1255 del TGCAGCC NA Anxiety related traits, association with Borroni et al., 2006 Albani et al., 2009
Number Of Location Repetition Sequence Reported Disease/Phenotype Referance Repetitions
Ogilvie et al., 21 Intron 2 (GGCTGYGACCYRGRRTG)n 10-12 Unipolar disorder, association with 1996 Allen et al., Pulmonary arterial hypertension, 22 Intron 2 (GGCTGYGACCYRGRRTG)n 12 2008: association with Cao et al., 2009
Table 2. Solute Carrier Family 6 Member 4 (SLC6A4) related mutations.
In a later study, the expression of the native SLC6A4 the early developmental period of mice, it was gene in cultured lymphoblast cell lines from subjects observed that adult mice exhibited abnormal with different SLC6A4 promoter genotypes was emotional behaviors. It has been reported that examined (Lesch et al., 1996).The mRNA serotonin plays a critical role in the maturation of concentration of the SLC6A4 gene in L/L cells was brain systems that regulate emotional function, and found to be 1.4 to 1.7-fold higher than the L/S and that the low expression level of the SLC6A4 gene S/S cells (Lesch et al., 1996). Bradley et al. (2005) may be related to the development of psychiatric directly measured serotonin transporter mRNA disorders in adults (Ansorge et al., 2004). A study of levels and also identified 4 loci containing the transgenic mice overexpressing the SLC6A4 gene serotonin transporter gene from 85 independent and wild-type mice showed that right ventricular lymphoblast lines. They found strong impact of 5- pressure was 3-fold higher in transgenic mice HTTLPR on the mRNA exression (Bradley et al., (Maclean et al., 2004). Page et al. (2009) reported 2005). macrocephaly in Pten +/- mice. Female Pten +/- mice The Gly56Ala substitution in the exon 2 of the had socialization disorder, whereas male Pten +/- SLC6A4 gene has been reported to be associated mice had no socialization disorder. This phenotype with autism and exhibit structurally high SERT was exacerbated in mice with Pten and SLC6A4 activity (Sutcliffe et al., 2005). I425V substitution in double haploinsufficiency. As a result of these the exon 9 of the SLC6A4 gene has been reported to findings PTEN and SLC6A4 genes have been be associated with obsessive-compulsive disorder reported to be associated with autism spectrum (OCD) (Ozaki et al., 2003; Kilic et al., 2003; Zhang disorder (ASD). et al., 2007). In addition, A-1438G and T102C polymorphisms were reported to be associated with Breast cancer OCD (Taylor, 2013; Taylor, 2016). Rao et al. (2017) High expression is found in breast cancer, but the reported that I550V (exon 12) and K605N (exon 13) gene product is not prognostic according to The substitutions of the SLC6A4 gene are associated Human Protein Atlas. with major depression disorder (MDD) and SA (non- A fusion gene PIP4K2B /SLC6A4 was found in fatal suicidal behavior) in addition to autism and breast cancer (Yoshida et al., 2013). OCD in 36 Chinese patients. Animal Experiments When 5-HTT was temporarily inhibited by fluoxetine (selective serotonin re-uptake inhibitor) in
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Obsessive-Compulsive Disorder postnatal depression (Sanjuan et al., 2008; (OCD) Oberlander et al., 2013). Interestingly, the genetic and epigenetic variations have been reported in the Hu et al. (2006) found that the gain-of-function SLC6A4 gene of children exposed to prenatal homozygous L(A)L(A) genotype was 2-fold in depression (Devlin et al., 2010; Oppenheimer et al., patients with OCD compared to healthy individuals. 2013; Wankerl et al., 2014; Babineau et al., 2014; In a replication study in 175 trios consisting of Green et al., 2017). 5-HTTLPR polymorphisms and probands with OCD and their parents, the L(A) allele DNA methylations of SLC6A4 gene have been was 2-fold overtransmitted to the patients with OCD. reported to be associated with depression (Devlin et The HTTLPR L(A)L(A) genotype exerted 1.8-fold al., 2010; Sugawara et al., 2013). effect on risk of OCD, thus establishing the role of the HTT gene in OCD. In another study, the Seasonal Affective Disorder (SAD) frequency of Stin2.12 allele in Asian patients with Willeit et al. (2003) genotyped 284 subjects (138 anxiety disorder (including OCD) was reported to be SAD patients and 146 healthy individuals) to significantly higher compared to the healthy examine the relationship between L and S-variants individuals (Ohara et al., 1998). There is also a in the 5-HTTLPR polymorphism of SLC6A4 gene possible association between OCD and Stin2.12 with SAD. The distribution of genotype and S allele allele in Spanish Caucasian population (Baca-Garcia frequency was found similar between patients and et al., 2007; Saiz et al., 2008). healthy subjects, while they were correlated with the Anxiety-Related Personality Traits subtypes of DSM-IV depression. L allele was correlated with melancholic depression whereas S The homozygous or heterozygous form of the S- allele was related to atypical depression. It was variant of the 5-HTTLPR polymorphism in the concluded that 5-HTTLPR polymorphism affects the SLC6A4 gene has been reported to be associated phenotypic disease expression but it is not the cause with lower expression and openness, and higher of disease. neuroticism (Lesch et al., 1996). Individuals with 1- The effects of light therapy on serotonin transporter 2 copies of the S-variant of the 5-HTTLPR binding (5-HTT BPND), which is biomarker of 5- polymorphism, which is implicated in reduced 5- HTT levels, in the anterior cingulate and prefrontal HTT expression and function and increased fear and cortices (ACC and PFC) of healthy individuals anxiety-related behaviours, demonstrated higher during the fall and winter was studied. In winter, amygdala activity in response to fearful stimuli light therapy significantly decreased 5-HTT BPND by compared with individuals homozygous for the L- 12% in the ACC with respect to placebo, whereas in variant (Hariri et al., 2002). The altered function of the fall, no significant change in 5-HTT BPND was the serotonin neurotransmission system causes measured. In this context, it has been reported that 5- aggressive behaviour in Alzheimer's patients (AD) HTT BPND can be used as a biomarker for the (Brown et al., 1982; Palmer et al., 1988). In a study assessment of the modification effects of light conducted on 137 AD patients, the aggressive therapy (Harrison et al., 2015). In a study on 20 SAD behaviours (58 patients) were associated with L/L patients and 20 healthy participants the impact of genotype (Sukonick et al., 2001). seasonal (winter and summer) variations on 5-HTT Major Depressive Disorder (MDD) activity was investigated by analysing brain 5-HTT People with L/S or S/S allele in stressful life BPND levels. The study reported a significant conditions have been reported to have more increase in 5-HTT BPND in different brain regions depression and suicidal tendency than those with L/L (including ACC and PFC) especially in severe SAD allele (Caspi et al., 2003). They also reported that the during winter. The 5-HTT BPND as biomarker in the individual's response to environmental insults was diagnosis of SAD is important as it can be applied determined by environmental-gene interaction for the development of prevention strategies against (Caspi et al., 2003). In a study conducted on disease progress (Tyrer et al., 2016). Pomerania population, the relationship of S-variant Alcoholism with environmental interaction and depression was A meta-analysis study (data from 3,489 alcoholics determined. The results of the study supported and 2,325 controls) was conducted on the association previous studies on the gene-environment of 5-HTTLPR polymorphisms of SLC6A4 with interaction of the S allele. It has also been revealed alcohol dependence. It has been reported that alcohol to cause high mental vulnerability to social stress and dependence complicated by a comorbid psychiatric chronic diseases (Grabe et al., 2005). Homozygous condition or a more severe form of alcoholism is or heterozygous genotypes of the S-variant were associated with the S-variant (Feinn et al., 2005). In associated with stress-related depression and anxiety a study conducted on university students, the S- disorders in elite athletes (Petito et al., 2016). The 5- variant was reported to be associated with high HTTLPR polymorphisms of the SLC6A4 gene have alcohol consumption (Herman et al., 2003). High been reported to be associated with prenatal and
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alcohol consumption in men with homozygous or DNA methylation analysis of lymphoblastic cell heterozygote genotypes of the S-variant has been lines (LCLs) revealed DNA hypermethylation in reported, whereas it was seen only in the SLC6A4 gene that can be an epigenetic mark heterozygous women (Munaf et al., 2005). In a study resulting from a G×E interaction leading to the conducted on 273 (78.5% male) alcoholic development of BPED (Sugawara et al., 2011). In a individuals of the Caucasus and Hispanic origin, it study on the association of SLC6A4 and DRD2 was reported that G allele carriers for the rs1042173 (dopamine D2 receptor) genes with BPED, the SNP in the 3'UTR region of the SLC6A4 gene had gender specific differences in SLC6A4 gene lower alcohol consumption than T-allele polymorphisms were reported. The results revealed homozygotes (Seneviratne et al., 2009). G allele gender-specific association of the DRD2 A1/A1 and transfection to HeLa cells resulted in higher mRNA the 5-HTTLPR S/S, S/LG, and LG/LG (S+) and protein expression compared to T allele genotypes in type I and type II men, but not in transfected cells (Seneviratne et al., 2009). women. A significant interaction for the DRD2 Sudden Infant Death Syndrome A1/A1 and 5-HTTLPR S+ polymorphisms was also found only in type I and type II men (Wang et al., (SIDS) 2014). L/L genotype and excess of L-variant have been reported to be associated with SIDS (Narita et al., Pulmonary Hypertension (PPH) 2001; Weese-Mayer et al., 2003). In addition, the Smooth muscle cells (SMC) of pulmonary artery in Stin2.12 allele has been associated with SIDS in PPH patients grow faster than controls when 5-HTT African-Americans and Japanese, whereas it is not expression is stimulated by serotonin. As a result of associated with SIDS in Caucasian-Americans these findings, 5-HTT has been shown to play a key (Narita et al., 2001; Weese-Mayer et al., 2003). role in the pathogenesis of SMC proliferation and 5- Panic Disorder (PD) HTT polymorphisms are associated with PHH (Eddahibi et al., 2001). The higher 5-HTT The rs3813034 variant in the 3'UTR region of the expression was reported in pulmonary artery SMC in SLC6A4 gene has been reported to be related to PD patients with L/L genotypes compared to L/S and (Gyawali et al., 2010). Decreased SLC6A4 gene S/S genotypes, resulting in more severe PPH. expression due to the gene polymorphisms in (Eddahibi et al., 2003). In a study on the association midbrain, hypothalamus and temporal lobe has been of idiopathic PPH with 5-HTT polymorphism in associated with PD (Maron et al., 2006). Strug et al. children, the L/L genotype has been reported to be (2010) reported that rs140701 variant of the associated with the aetiology of PPH (Vachharajani SLC6A4 gene may be associated with PD. and Saunders, 2005). Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness (MDI) References The disorder of the neurotransmitter system, Adamsen D, Meili D, Blau N, Thöny B, Ramaekers V. including serotonin and monoamines, has been Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5- reported to be associated with bipolar disorder (Scott HTTLPR L/L promoter variants. Mol Genet Metab. 2011 et al., 1979; Kapur and Remington, 1992). The Mar;102(3):368-73 patients with BPAD without panic disorder exhibited Ahmed BA, Bukhari IA, Jeffus BC, Harney JT, Thyparambil statistically higher frequencies of the Catechol O- S, Ziu E, Fraer M, Rusch NJ, Zimniak P, Lupashin V, Tang Methyltransferase (COMT) Met158 and the S- D, Kilic F. The cellular distribution of serotonin transporter is variant 5-HTTLPR genotypes with respect to healthy impeded on serotonin-altered vimentin network. PLoS One. individuals (Rotondo et al., 2002). When the 2009;4(3):e4730 relationship between L and S-variant Ahmed BA, Jeffus BC, Bukhari SI, Harney JT, Unal R, polymorphisms of SLC6A4 gene and BPAD and Lupashin VV, van der Sluijs P, Kilic F. Serotonin transamidates Rab4 and facilitates its binding to the C unipolar depression were investigated by meta- terminus of serotonin transporter. J Biol Chem. 2008 Apr analysis study, it was revealed that the S-variant 4;283(14):9388-98 could be associated with BPAD but not with unipolar Albani D, Vittori A, Batelli S, Polito L, De Mauro S, depression. The L-variant was not implicated in Galimberti D, Scarpini E, Lovati C, Mariani C, Forloni G. BPAD and/or unipolar depression (Lasky-Su et al., Serotonin transporter gene polymorphic element 5-HTTLPR 2005). However other studies reported no significant increases the risk of sporadic Parkinson's disease in Italy. relationship between SLC6A4 5-HTTLPR and Eur Neurol. 2009;62(2):120-3 VNTR polymorphisms and BPAD (Mendlewicz et Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura al., 2004; Cho et al., 2005). The association between FK, Khoury MJ, Tanzi RE, Bertram L. Systematic meta- epigenetic variations of SLC6A4 gene and BPAD analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008 were studied on 20 bipolar monozygotic twins with Jul;40(7):827-34 respect to 20 healthy subjects. The promoter-wide
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Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life Cho HJ, Meira-Lima I, Cordeiro Q, Michelon L, Sham P, blockade of the 5-HT transporter alters emotional behavior Vallada H, Collier DA. Population-based and family-based in adult mice Science 2004 Oct studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis 29;306(5697):879-81 Mol Psychiatry 2005 Aug;10(8):771-81 Aoki J, Ikeda K, Murayama O, Yoshihara E, Ogai Y, Devlin AM, Brain U, Austin J, Oberlander TF. Prenatal Iwahashi K. The association between personality, pain exposure to maternal depressed mood and the MTHFR threshold and a single nucleotide polymorphism C677T variant affect SLC6A4 methylation in infants at birth (rs3813034) in the 3'-untranslated region of the serotonin PLoS One 2010 Aug 16;5(8):e12201 transporter gene (SLC6A4) J Clin Neurosci 2010 May;17(5):574-8 Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S. Babineau V, Green CG, Jolicoeur-Martineau A, Bouvette- Serotonin transporter overexpression is responsible for Turcot AA, Minde K, Sassi R, St-André M, Carrey N, pulmonary artery smooth muscle hyperplasia in primary Atkinson L, Kennedy JL, Lydon J, Steiner M, Gaudreau H, pulmonary hypertension J Clin Invest 2001 Levitan R, Meaney M, Wazana A; MAVAN project. Prenatal Oct;108(8):1141-50 depression and 5-HTTLPR interact to predict dysregulation from 3 to 36 months--a differential susceptibility model J Esterling LE, Yoshikawa T, Turner G, Badner JA, Bengel D, Child Psychol Psychiatry 2015 Jan;56(1):21-9 Gershon ES, Berrettini WH, Detera-Wadleigh SD. Serotonin transporter (5-HTT) gene and bipolar affective disorder Am Baca-Garcia E, Vaquero-Lorenzo C, Diaz-Hernandez M, J Med Genet 1998 Feb 7;81(1):37-40 Rodriguez-Salgado B, Dolengevich-Segal H, Arrojo- Romero M, Botillo-Martin C, Ceverino A, Piqueras JF, Feinn R, Nellissery M, Kranzler HR. Meta-analysis of the Perez-Rodriguez MM, Saiz-Ruiz J. 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Aggression, suicide, and interacting with social stressors and chronic disease burden serotonin: relationships to CSF amine metabolites Am J Mol Psychiatry 2005 Feb;10(2):220-4 Psychiatry 1982 Jun;139(6):741-6 Green CG, Babineau V, Jolicoeur-Martineau A, Bouvette- Camarena B, González L, Hernández S, Caballero A. Turcot AA, Minde K, Sassi R, St-André M, Carrey N, SLC6A4 rare variant associated with eating disorders in Atkinson L, Kennedy JL, Steiner M, Lydon J, Gaudreau H, Mexican patients J Psychiatr Res 2012 Aug;46(8):1106-7 Burack JA, Levitan R, Meaney MJ, Wazana A; Maternal Adversity, Vulnerability, and Neurodevelopment Research Canli T, Lesch KP. Long story short: the serotonin Team. 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prefrontal cortex Acta Psychiatr Scand 2015 has allele-dependent differential enhancer-like properties in Nov;132(5):379-88 the mouse embryo Proc Natl Acad Sci U S A 1999 Dec 21;96(26):15251-5 Hartley CA, McKenna MC, Salman R, Holmes A, Casey BJ, Phelps EA, Glatt CE. Serotonin transporter polyadenylation MacLean MR, Deuchar GA, Hicks MN, Morecroft I, Shen S, polymorphism modulates the retention of fear extinction Sheward J, Colston J, Loughlin L, Nilsen M, Dempsie Y, memory Proc Natl Acad Sci U S A 2012 Apr Harmar A. Overexpression of the 5-hydroxytryptamine 3;109(14):5493-8 transporter gene: effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension Circulation 2004 Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, May 4;109(17):2150-5 Lesch KP. Allelic variation of human serotonin transporter gene expression J Neurochem 1996 Jun;66(6):2621-4 Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely Herman AI, Philbeck JW, Vasilopoulos NL, Depetrillo PB. RD, Gershon MD. Serotonin transporter variant drives Serotonin transporter promoter polymorphism and preventable gastrointestinal abnormalities in development differences in alcohol consumption behaviour in a college and function J Clin Invest 2016 Jun 1;126(6):2221-35 student population Alcohol Alcohol 2003 Sep- Oct;38(5):446-9 Maron E, Shlik J. Serotonin function in panic disorder: important, but why? Neuropsychopharmacology 2006 Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Jan;31(1):1-11 Review Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D. 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OPEN ACCESS JOURNAL INIST-CNRS Leukaemia Section Short Communication t(6;12)(q22;p13) ETV6/FRK Tatiana Gindina R.M. Gorbacheva Memorial Institute of Children Oncology Hematology and Transplantation at First Pavlov Saint-Petersburg State Medical University, Saint-Petersburg, Russia / [email protected] Published in Atlas Database: February 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0612q21p13ETV6FRKID1322.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70649/02-2019-t0612q21p13ETV6FRKID1322.pdf DOI: 10.4267/2042/70649 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract NHL. Review on t(6;12)(q21;p13), with data on the genes Acute lymphoblastic leukemia (ALL) was involved diagnosed in 6 pediatric patients, 4 of them were Keywords with early pre-B ALL (Raimondi et al., 1997; Hayashi et al., 1990), one patient with T-ALL chromosome 6; chromosome 12; acute (Kaneko et al., 1989). lymphoblastic leukemia; acute myeloid leukemia; Acute myeloid leukemia (AML): there were 2 adult ETV6; FRK patients (Hosoya et al., 2005; Campbell et al., 1994). Small lymphocytic lymphoma was diagnosed in 1 Clinics and pathology patient (Bloomfield et al., 1983). Disease Epidemiology Translocation t(6;12)(q21;p13) is a rare abnormality, The t(6;12)(q21;p13) is a rare reciprocal it occurs in both myeloid and lymphoid disorders translocation. Male predominance (Male : Female including AML, ALL, and 3,5 : 1). Age, # Diseasenbsp; Karyotype Author gender 1 7, M Early pre-B ALL 48,XY,t(6;12)(q21;p13),+16,+add(19)(p13) Raimondi et al, 1997 46,XY,inv(12)(p13q22),add(21)(q22)/46,idem,t(6;12)(q21;p13)/46,XY,t(6;1 2 5,5, M Early pre-B ALL Raimondi et al, 1997 2),inv(12) 3 ?, M ALL 46,XY,t(6;12)(q21;pl3)/46,XY Katz et al, 1991 48,XY.+16,+der(19)t(19;?)(p13;?),t(6:12)(q21;p13)/48XY,+16,+der(19),d 4 ?, M Early pre-B ALL Hayashi et al., 1990 e1(12)(p12),t(6;12) 46,XY,inv(12)(p13q22).- 5 ?, M Early pre-B ALL 21,+der(21)t(21;?)(q22;?)/46,XY,t(6;12)(q21:p13),inv(12),- Hayashi et al., 1990 21,+der(21)/46,XY,t(6;12),inv(12) 6 10, F T-cell ALL 46,XX,t(6;12)(q21;p13),t(7;14)(p15;q32) Kaneko et al., 1989 43-44,XY,-4,-7,-9,-11,-13,- Small Lymphocytic 7 69, M 17,t(1;14)(p32;q32),t(6;12)(q21;p13),+der(7)t(7;?)(p22;?)+der(13)t(13;?)(q3 Bloomfield 1983 Lymphoma 4;?),+der(17)t(17;17)(p13;?),+20 8 69, F AML 46,XX,t(6;12)(q21;p13) Hosoya et al., 2005 AML with 54,XY,t(6;12)(q21;p13),+8,+9,+10,+11,+13,+14,add(17)(p11),+20,+del(20)( 9 55, M maturation Campbell et al., 1994 q11),+21 (FAB type M2)
Table 1. Reported cases with t(6;12)(q21;p13).
Atlas Genet Cytogenet Oncol Haematol. 2020; 24(1) 51 t(6;12)(q22;p13) ETV6/FRK Gindina T
Prognosis FRK (Fyn-related Src family tyrosine Survival in ALL and AML patients was 40, 106+ and kinase) 5 months respectively (Raimondi et al, 1997; Hosoya Location 6q22.1 et al, 2005). Protein FRK belongs to a family of SRC kinases. SRC is the Cytogenetics prototype for a family of genes that encode non- receptor tyrosine kinases implicated in a variety of Additional anomalies cellular processes. The wild type FRK is expressed Sole abnormality in 2 patients (1 ALL, 1 AML). primarily in epithelial tissues, but also weakly in the Additional chromosome anomalies were observed in various hematopoietic cell lines. However, its 6/8 patients. functions or downstream signaling pathways remain In early pre B-ALL t(6;12)(q21;p13) was associated largely unknown, especially in hematopoietic in combination with extra chromosome 16 in 2 systems. The only known candidate endogenous patients, and a complex karyotype in 2 cases downstream component of FRK is the SH2-domain (Hayashi et al., 1990; Raimondi et al., 1997). In adaptor protein SHB (Hosoya et al., 2005). small lymphocytic lymphoma, t(6;12)(q21;p13) is part of a complex karyotype. Result of the chromosomal Genes involved and anomaly proteins Hybrid gene In the resultant ETV6/FRK fusion protein, the entire ETV6 (ets variant 6) PNT oligomerization domain of ETV6 and the Location 12p13.2 kinase domain of FRK are fused in frame. Protein Fusion protein ETV6 encodes an ETS family transcription factor. ETV6 protein contains two functional domains: a N- Oncogenesis terminal pointed (PNT) domain that is involved in It has been shown that ETV6/FRK is an oncoprotein protein-protein interactions with other proteins, and with dual functions: deregulated tyrosine kinase a C-terminal DNA-binding domain. activity and a dominant-negative modulation of Gene knockout studies suggest that it is required for transcriptional repression by ETV6. Because wild- hematopoiesis and maintenance of the developing type ETV6 appears to have tumor-suppressive vascular network. activity, its suppression by ETV6/ FRK also could ETV6 is known to be involved in a large number of contribute to oncogenesis (Hosoya et al., 2005). chromosomal abnormalities associated with leukemia and inborn fibrosarcoma.
Figure 1. Schematic representation of wild-type ETV6, FRK, and the fusion transcript ETV6/FRK. The breakpoints are indicated by vertical arrows.
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t(6;12)(q22;p13) ETV6/FRK Gindina T
Kaneko Y, Frizzera G, Shikano T, Kobayashi H, Maseki N, Sakurai M. Chromosomal and immunophenotypic patterns References in T cell acute lymphoblastic leukemia (T ALL) and Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson lymphoblastic lymphoma (LBL). Leukemia. 1989 BA, Gajl-Peczalska KJ. Nonrandom chromosome Dec;3(12):886-92 abnormalities in lymphoma. Cancer Res. 1983 Katz JA, Tayloor LD, Carroll A, Elder FF, Mahoney DH.. Jun;43(6):2975-84 Cytogenetic features of childhood acute lymphoblastic Campbell LJ, Garson OM. The prognostic significance of leukemia. A concordance study and a Pediatric Oncology deletion of the long arm of chromosome 20 in myeloid Group study. Cancer Genet Cytogenet. 1991;55(2):249-56. disorders. Leukemia. 1994 Jan;8(1):67-71 Raimondi SC, Shurtleff SA, Downing JR, Rubnitz J, Mathew Hayashi Y, Raimondi SC, Look AT, Behm FG, Kitchingman S, Hancock M, Pui CH, Rivera GK, Grosveld GC, Behm GR, Pui CH, Rivera GK, Williams DL. Abnormalities of the FG.. 12p abnormalities and the TEL gene (ETV6) in long arm of chromosome 6 in childhood acute lymphoblastic childhood acute lymphoblastic leukemia. Blood. leukemia. Blood. 1990 Oct 15;76(8):1626-30 1997;90(11):4559-66. Hosoya N, Qiao Y, Hangaishi A, Wang L, Nannya Y, This article should be referenced as such: Sanada M, Kurokawa M, Chiba S, Hirai H, Ogawa S. Identification of a SRC-like tyrosine kinase gene, FRK, Gindina T. t(6;12)(q22;p13) ETV6/FRK. Atlas Genet fused with ETV6 in a patient with acute myelogenous Cytogenet Oncol Haematol. 2020; 24(1):51-53. leukemia carrying a t(6;12)(q21;p13) translocation. Genes Chromosomes Cancer. 2005 Mar;42(3):269-79
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