DOCSLIB.ORG

Germline-Derived Gain-Of-Function Variants of Gsa-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Germline-Derived Gain-Of-Function Variants of Gsa-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis CLINICAL RESEARCH www.jasn.org Germline-Derived Gain-of-Function Variants of Gsa-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis Mami Miyado,1 Maki Fukami,1 Shuji Takada,2 Miho Terao,2 Kazuhiko Nakabayashi,3 Kenichiro Hata,3 Yoichi Matsubara,4 Yoko Tanaka ,5 Goro Sasaki,5 Keisuke Nagasaki ,6 Masaaki Shiina,7 Kazuhiro Ogata,7 Youhei Masunaga,8 Hirotomo Saitsu,9 and Tsutomu Ogata 1,8 Departments of 1Molecular Endocrinology, 2Systems BioMedicine, 3Maternal-Fetal Biology and 4Head Office, National Research Institute for Child Health and Development, Tokyo, Japan; 5Department of Pediatrics, Tokyo Dental College, Ichikawa General Hospital, Ichikawa, Japan; 6Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 7Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan; and Departments of 8Pediatrics and 9Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan ABSTRACT Background The stimulatory G-protein a-subunit encoded by GNAS exons 1–13 (GNAS-Gsa)mediates signal transduction of multiple G protein–coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gsa variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respec- tively. Specific somatic gain-of-function GNAS-Gsa variants have been detected in McCune–Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality. Methods We performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants. Results Whole-exome sequencing revealed two GNAS-Gsa candidate variants for NSIAD: GNAS-Gsa p.(F68_G70del) in one family and GNAS-Gsa p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gsa alone was involved in AVPR2 sig- naling and shared by the families. Protein structural analyses revealed a gain-of-function–compatible con- formational property for p.M255V-Gsa, although such assessment was not possible for p.F68_G70del-Gsa. Both variants had gain-of-function effects that were significantly milder than those of McCune–Albright syndrome–specific somatic Gsa variants. Model mice for p.F68_G70del-Gsa showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gsa exhibited severe failure to thrive. Conclusions This study shows that germline-derived gain-of-function rare variants of GNAS-Gsa exist and cause NSIAD as a novel Gsa-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gsa’s gain-of-function effects. J Am Soc Nephrol 30: 877–889, 2019. doi: https://doi.org/10.1681/ASN.2018121268 CLINICAL RESEARCH Received December 27, 2018. Accepted February 2, 2019. Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan, or Prof. Tsutomu Ogata, Department of Pediatrics, Hamamatsu M.M. and M.F. contributed equally to this work. University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. Email: [email protected] or Published online ahead of print. Publication date available at [email protected] www.jasn.org. Copyright © 2019 by the American Society of Nephrology Correspondence: Dr. Maki Fukami, Department of Molecular Endocrinology, National Research Institute for Child Health and J Am Soc Nephrol 30: 877–889, 2019 ISSN : 1046-6673/3005-877 877 CLINICAL RESEARCH www.jasn.org The GNAS complex locus generates multiple gene products, Significance Statement including the stimulatory G-protein a-subunit encoded by GNAS exons 1–13 (GNAS-Gsa).1,2 GNAS-Gsa is biallelically The stimulatory G-protein a-subunit GNAS-Gsa mediates signal expressed in most tissues, including the renal collecting transduction of multiple G protein–coupled receptors, including fi duct, and it is predominantly expressed from the maternal arginine vasopressin receptor 2 (AVPR2). Speci c gain-of-function variants in AVPR2 are known causes of nephrogenic syndrome allele in a few tissues, such as the renal proximal tubule, of inappropriate antidiuresis (NSIAD), an arginine vasopressin– – thyroid, gonad, and pituitary.1 5 G-protein a-subunit (Gsa) independent antidiuresis. In two families with NSIAD, after ex- mediates signal transductions of multiple G protein–coupled cluding AVPR2 gain-of-function variants, the authors identified two receptors, including parathyroid hormone 1 receptor (PTH1R), novel germline-derived variants of GNAS-Gsa. They also showed GNAS thyroid-stimulating hormone receptor (TSHR), follicle- that both of the -Gsa variants had gain-of-function effects that were milder than those of specific somatic GNAS-Gsa variants stimulating hormone receptor (FSHR), luteinizing hormone/ reported in McCune–Albright syndrome, a condition that may re- choriogonadotropin receptor (LHCGR), growth hormone– sult in renal phosphate wasting. The results refute the widely be- releasing hormone receptor (GHRHR), and arginine vasopres- lieved concept that a germline-derived GNAS-Gsa gain-of-function sin receptor 2 (AVPR2).6 To date, various germline-derived variant is absent because of embryonic lethality and reveal the loss-of-function (LOF) variants of GNAS-Gsa of maternal and genetic heterogeneity in NSIAD. paternal origin have been found in pseudohypoparathyroidism type Ia (PHP-Ia) and pseudopseudohypoparathyroidism Oligonucleotides (PPHP), respectively,1,2,6,7 and specific somatic gain-of-function Oligonucleotides used in this study are shown in Supplemental (GOF) variants of GNAS-Gsa, such as p.R201C and p.R201H, Table 1. have been detected in McCune–Albright syndrome (MAS) and endocrine tumors.1,6,8 However, no germline-derived GOF var- Molecular Diagnostic Studies iant of GNAS-Gsa has been identified, implying that such a We performed Sanger sequencing, genome-wide array com- variant causes embryonic lethality.9 parative genomic hybridization (aCGH), and whole-exome Nephrogenic syndrome of inappropriate antidiuresis sequencing (WES) using leukocyte genomic DNA samples. (NSIAD) is a rare disorder caused by impaired renal capacity Sanger sequencing was carried out for all of the coding exons to excrete a free water load into the urine under undetectable or and their splice sites of AVPR2 and for variant-positive GNAS- very low plasma arginine vasopressin (AVP) values.10 Although Gsa exons on the ABI 3130xl Genetic Analyzer (Thermo this condition is associated with blood hypo-osmolality and Fisher Scientific). To confirm heterozygous variants, sequenc- hyponatremia as well as inappropriately elevated urine osmo- ing was performed for subcloned wild-type (WT) and variant lality and sodium concentration as observed in the syndrome alleles. of inappropriate antidiuretic hormone secretion (SIADH),11 Genome-wide aCGH was performed with a catalog human NSIAD and SIADH show a sharp contrast in the plasma array (131M format; ID G4447A) according to the manufac- AVP/ADH value. Consistent withsuchanAVP-independent turer’s instructions (Agilent Technologies). Obtained data antidiuresis, NSIAD has been shown to be caused by specific were analyzed using the default settings of the Agilent Geno- GOF variants of AV PR2, such as p.R137C, p.R137L, and mic Workbench 7.0. Copy number alterations were regarded p.F229V.10,12 as normal variants if they had been registered in Database of Here, we report relatively mild germline-derived GOF var- Genomic Variants (http://dgv.tcag.ca/dgv/app/home) or Clin- iants of GNAS-Gsa identified in two families with NSIAD as a Var (http://www.ncbi.nlm.nih.gov/clinvar/). salient phenotype. This study demonstrates the presence of WES was carried out using SureSelect Human All Exon V6 germline-derived GOF variants of GNAS-Gsa and establishes (Agilent Technologies). Captured libraries were sequenced by a novel Gsa-mediated genetic disease. NextSeq 500 (Illumina) with 150-bp paired end reads. Reads were aligned to the reference genome (Human GRCh37/hg19; http://genome.ucsc.edu/) using BWA-MEM (Version 0.7.12) METHODS with default parameters. Duplicated reads were removed by Picard (Version 2.9.2), and local realignment and base quality Ethical Approval recalibration were performed by GATK Version 3.7. Variants Human studies were approved by the Institutional Review were identified with the GATK HaplotypeCaller, and those Board Committees at Hamamatsu University School of Med- with minor allele frequencies of ,0.005 in all of the following icine (91–002) and National Research Institute for Child public databases (the whole-genome and exome data for the Health and Development (519), and they were performed East Asian population in the Genome Aggregation Database after obtaining written informed consent. Mouse studies [gnomAD_genome_EAS andgnomAD_exome_EAS],13 the were approved by the Animal Care and Use Committee of Human Genetic Variation Database,14 allele frequency data National Research Institute for Child Health and Develop- of 2049 Japanese individuals,15 and in-house database) were ment (A2014–001), and they were conducted in accordance selected as rare variants. Final variants were annotated with with the approved protocols. Annovar.16 In silico pathogenicity
Load more

Recommended publications
  • Product Description SALSA® MS-MLPA® Probemix ME031-C1 GNAS to Be Used with the MS-MLPA General Protocol
    Product description version C1-01; Issued 19 March 2021 Product Description SALSA® MS-MLPA® Probemix ME031-C1 GNAS To be used with the MS-MLPA General Protocol. Version C1 As compared to version B2, probemix completely revised, details are shown in complete product history see page 11. Catalogue numbers: ME031-025R: SALSA MS-MLPA Probemix ME031 GNAS, 25 reactions. ME031-050R: SALSA MS-MLPA Probemix ME031 GNAS, 50 reactions. ME031-100R: SALSA MS-MLPA Probemix ME031 GNAS, 100 reactions. To be used in combination with a SALSA MLPA reagent kit, SALSA HhaI (SMR50) and Coffalyser.Net data analysis software. MLPA reagent kits are either provided with FAM or Cy5.0 dye-labelled PCR primer, suitable for Applied Biosystems and Beckman/SCIEX capillary sequencers, respectively (see www.mrcholland.com). Certificate of Analysis Information regarding storage conditions, quality tests, and a sample electropherogram from the current sales lot is available at www.mrcholland.com. Precautions and warnings For professional use only. Always consult the most recent product description AND the MS-MLPA General Protocol before use: www.mrcholland.com. It is the responsibility of the user to be aware of the latest scientific knowledge of the application before drawing any conclusions from findings generated with this product. This SALSA MS-MLPA probemix is intended for experienced MLPA users only! The exact link between the GNAS complex locus genotype and phenotype is still being investigated. Use of this ME031 GNAS probemix will not always provide you with clear-cut answers and interpretation of results can therefore be complicated. MRC Holland can only provide limited support with interpretation of results obtained with this product, and recommends thoroughly screening any available literature.
    [Show full text]
  • Functional Characterisation of Human Synaptic Genes Expressed in the Drosophila Brain Lysimachos Zografos1,2, Joanne Tang1, Franziska Hesse3, Erich E
    © 2016. Published by The Company of Biologists Ltd | Biology Open (2016) 5, 662-667 doi:10.1242/bio.016261 METHODS & TECHNIQUES Functional characterisation of human synaptic genes expressed in the Drosophila brain Lysimachos Zografos1,2, Joanne Tang1, Franziska Hesse3, Erich E. Wanker3, Ka Wan Li4, August B. Smit4, R. Wayne Davies1,5 and J. Douglas Armstrong1,5,* ABSTRACT systems biology approaches are likely to be the best route to unlock a Drosophila melanogaster is an established and versatile model new generation of neuroscience research and CNS drug organism. Here we describe and make available a collection of development that society so urgently demands (Catalá-López transgenic Drosophila strains expressing human synaptic genes. The et al., 2013). Yet these modelling type approaches also need fast, collection can be used to study and characterise human synaptic tractable in vivo models for validation. genes and their interactions and as controls for mutant studies. It was More than 100 years after the discovery of the white gene in generated in a way that allows the easy addition of new strains, as well Drosophila melanogaster, the common fruit fly remains a key tool as their combination. In order to highlight the potential value of the for the study of neuroscience and neurobiology. The fruit fly collection for the characterisation of human synaptic genes we also genome is well annotated and there is a vast genetic manipulation use two assays, investigating any gain-of-function motor and/or toolkit available. This allows interventions such as high throughput cognitive phenotypes in the strains in this collection. Using these cloning (Bischof et al., 2013; Wang et al., 2012) and the precise assays we show that among the strains made there are both types of insertion of transgenes in the genome (Groth et al., 2004; Venken gain-of-function phenotypes investigated.
    [Show full text]
  • HCC and Cancer Mutated Genes Summarized in the Literature Gene Symbol Gene Name References*
    HCC and cancer mutated genes summarized in the literature Gene symbol Gene name References* A2M Alpha-2-macroglobulin (4) ABL1 c-abl oncogene 1, receptor tyrosine kinase (4,5,22) ACBD7 Acyl-Coenzyme A binding domain containing 7 (23) ACTL6A Actin-like 6A (4,5) ACTL6B Actin-like 6B (4) ACVR1B Activin A receptor, type IB (21,22) ACVR2A Activin A receptor, type IIA (4,21) ADAM10 ADAM metallopeptidase domain 10 (5) ADAMTS9 ADAM metallopeptidase with thrombospondin type 1 motif, 9 (4) ADCY2 Adenylate cyclase 2 (brain) (26) AJUBA Ajuba LIM protein (21) AKAP9 A kinase (PRKA) anchor protein (yotiao) 9 (4) Akt AKT serine/threonine kinase (28) AKT1 v-akt murine thymoma viral oncogene homolog 1 (5,21,22) AKT2 v-akt murine thymoma viral oncogene homolog 2 (4) ALB Albumin (4) ALK Anaplastic lymphoma receptor tyrosine kinase (22) AMPH Amphiphysin (24) ANK3 Ankyrin 3, node of Ranvier (ankyrin G) (4) ANKRD12 Ankyrin repeat domain 12 (4) ANO1 Anoctamin 1, calcium activated chloride channel (4) APC Adenomatous polyposis coli (4,5,21,22,25,28) APOB Apolipoprotein B [including Ag(x) antigen] (4) AR Androgen receptor (5,21-23) ARAP1 ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 1 (4) ARHGAP35 Rho GTPase activating protein 35 (21) ARID1A AT rich interactive domain 1A (SWI-like) (4,5,21,22,24,25,27,28) ARID1B AT rich interactive domain 1B (SWI1-like) (4,5,22) ARID2 AT rich interactive domain 2 (ARID, RFX-like) (4,5,22,24,25,27,28) ARID4A AT rich interactive domain 4A (RBP1-like) (28) ARID5B AT rich interactive domain 5B (MRF1-like) (21) ASPM Asp (abnormal
    [Show full text]
  • Identification of Key Genes and Pathways for Alzheimer's Disease
    Biophys Rep 2019, 5(2):98–109 https://doi.org/10.1007/s41048-019-0086-2 Biophysics Reports RESEARCH ARTICLE Identification of key genes and pathways for Alzheimer’s disease via combined analysis of genome-wide expression profiling in the hippocampus Mengsi Wu1,2, Kechi Fang1, Weixiao Wang1,2, Wei Lin1,2, Liyuan Guo1,2&, Jing Wang1,2& 1 CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China 2 Department of Psychology, University of Chinese Academy of Sciences, Beijing 10049, China Received: 8 August 2018 / Accepted: 17 January 2019 / Published online: 20 April 2019 Abstract In this study, combined analysis of expression profiling in the hippocampus of 76 patients with Alz- heimer’s disease (AD) and 40 healthy controls was performed. The effects of covariates (including age, gender, postmortem interval, and batch effect) were controlled, and differentially expressed genes (DEGs) were identified using a linear mixed-effects model. To explore the biological processes, func- tional pathway enrichment and protein–protein interaction (PPI) network analyses were performed on the DEGs. The extended genes with PPI to the DEGs were obtained. Finally, the DEGs and the extended genes were ranked using the convergent functional genomics method. Eighty DEGs with q \ 0.1, including 67 downregulated and 13 upregulated genes, were identified. In the pathway enrichment analysis, the 80 DEGs were significantly enriched in one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, GABAergic synapses, and 22 Gene Ontology terms. These genes were mainly involved in neuron, synaptic signaling and transmission, and vesicle metabolism. These processes are all linked to the pathological features of AD, demonstrating that the GABAergic system, neurons, and synaptic function might be affected in AD.
    [Show full text]
  • Impaired Iloprost-Induced Platelet Inhibition and Phosphoproteome Changes in Patients with Confirmed Pseudohypoparathyroidism Ty
    www.nature.com/scientificreports OPEN Impaired iloprost‑induced platelet inhibition and phosphoproteome changes in patients with confrmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS Frauke Swieringa1,2, Fiorella A. Solari1,9, Oliver Pagel1,9, Florian Beck1, Jingnan Huang1,2, Marion A. H. Feijge2, Kerstin Jurk4, Irene M. L. W. Körver‑Keularts5, Nadine J. A. Mattheij2, Jörg Faber3, Joachim Pohlenz3, Alexandra Russo3, Connie T. R. M. Stumpel5,6, Dirk E. Schrander7, Barbara Zieger8, Paola E. J. van der Meijden2, René P. Zahedi1, Albert Sickmann1 & Johan W. M. Heemskerk2* Patients diagnosed with pseudohypoparathyroidism type Ia (PHP Ia) sufer from hormonal resistance and abnormal postural features, in a condition classifed as Albright hereditary osteodystrophy (AHO) syndrome. This syndrome is linked to a maternally inherited mutation in the GNAS complex locus, encoding for the GTPase subunit Gsα. Here, we investigated how platelet phenotype and omics analysis can assist in the often difcult diagnosis. By coupling to the IP receptor, Gsα induces platelet inhibition via adenylyl cyclase and cAMP-dependent protein kinase A (PKA). In platelets from seven patients with suspected AHO, one of the largest cohorts examined, we studied the PKA-induced phenotypic changes. Five patients with a confrmed GNAS mutation, displayed impairments in Gsα- dependent VASP phosphorylation, aggregation, and microfuidic thrombus formation. Analysis of the platelet phosphoproteome revealed 2,516 phosphorylation sites, of which 453 were regulated by Gsα-PKA. Common changes in the patients were: (1) a joint panel of upregulated and downregulated phosphopeptides; (2) overall PKA dependency of the upregulated phosphopeptides; (3) links to key platelet function pathways. In one patient with GNAS mutation, diagnosed as non‑AHO, the changes in platelet phosphoproteome were reversed.
    [Show full text]
  • Epigenetic Modifications to Cytosine and Alzheimer's Disease
    University of Kentucky UKnowledge Theses and Dissertations--Chemistry Chemistry 2017 EPIGENETIC MODIFICATIONS TO CYTOSINE AND ALZHEIMER’S DISEASE: A QUANTITATIVE ANALYSIS OF POST-MORTEM TISSUE Elizabeth M. Ellison University of Kentucky, [email protected] Digital Object Identifier: https://doi.org/10.13023/ETD.2017.398 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Ellison, Elizabeth M., "EPIGENETIC MODIFICATIONS TO CYTOSINE AND ALZHEIMER’S DISEASE: A QUANTITATIVE ANALYSIS OF POST-MORTEM TISSUE" (2017). Theses and Dissertations--Chemistry. 86. https://uknowledge.uky.edu/chemistry_etds/86 This Doctoral Dissertation is brought to you for free and open access by the Chemistry at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Chemistry by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • Supplemental Table 1A. Differential Gene Expression Profile of Adehcd40l and Adehnull Treated Cells Vs Untreated Cells
    Supplemental Table 1a. Differential Gene Expression Profile of AdEHCD40L and AdEHNull treated cells vs Untreated Cells Fold change Regulation Fold change Regulation ([AdEHCD40L] vs ([AdEHCD40L] ([AdEHNull] vs ([AdEHNull] vs Probe Set ID [Untreated]) vs [Untreated]) [Untreated]) [Untreated]) Gene Symbol Gene Title RefSeq Transcript ID NM_001039468 /// NM_001039469 /// NM_004954 /// 203942_s_at 2.02 down 1.00 down MARK2 MAP/microtubule affinity-regulating kinase 2 NM_017490 217985_s_at 2.09 down 1.00 down BAZ1A fibroblastbromodomain growth adjacent factor receptorto zinc finger 2 (bacteria-expressed domain, 1A kinase, keratinocyte NM_013448 /// NM_182648 growth factor receptor, craniofacial dysostosis 1, Crouzon syndrome, Pfeiffer 203638_s_at 2.10 down 1.01 down FGFR2 syndrome, Jackson-Weiss syndrome) NM_000141 /// NM_022970 1570445_a_at 2.07 down 1.01 down LOC643201 hypothetical protein LOC643201 XM_001716444 /// XM_001717933 /// XM_932161 231763_at 3.05 down 1.02 down POLR3A polymerase (RNA) III (DNA directed) polypeptide A, 155kDa NM_007055 1555368_x_at 2.08 down 1.04 down ZNF479 zinc finger protein 479 NM_033273 /// XM_001714591 /// XM_001719979 241627_x_at 2.15 down 1.05 down FLJ10357 hypothetical protein FLJ10357 NM_018071 223208_at 2.17 down 1.06 down KCTD10 potassium channel tetramerisation domain containing 10 NM_031954 219923_at 2.09 down 1.07 down TRIM45 tripartite motif-containing 45 NM_025188 242772_x_at 2.03 down 1.07 down Transcribed locus 233019_at 2.19 down 1.08 down CNOT7 CCR4-NOT transcription complex, subunit 7 NM_013354
    [Show full text]
  • Jcem1109.Pdf
    JCEM ONLINE Advances in Genetics—Endocrine Research Identification of Gene Expression Profiles Associated With Cortisol Secretion in Adrenocortical Adenomas Hortense Wilmot Roussel,* Delphine Vezzosi,* Marthe Rizk-Rabin, Olivia Barreau, Bruno Ragazzon, Fernande René-Corail, Aurélien de Reynies, Jérôme Bertherat, and Guillaume Assie´ Institut National de la Santé et de la Recherche Médicale Unité 1016 (H.W.R., D.V., M.R.-R., O.B., B.R., Downloaded from https://academic.oup.com/jcem/article/98/6/E1109/2536811 by guest on 28 September 2021 F.R.-C., J.B., G.A.); Institut Cochin, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104 (H.W.R., D.V., M.R.-R, O.B., B.R., F.R.-C., J.B., G.A.); and Department of Endocrinology (H.W.R., O.B., J.B., G.A.), Reference Center for Rare Adrenal Diseases (J.B.), Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France; Faculté de Médecine Paris Descartes (H.W.R., D.V., M.R.-R., O.B., B.R., F.R.-C., J.B., G.A.), Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Department of Endocrinology (D.V.), Hôpital Larrey, 31480 Toulouse, France; and Plateforme de Bioinformatique (A.d.R.), Carte d’Identité des Tumeurs, Ligue Contre le Cancer, 75013 Paris, France Context: The cortisol secretion of adrenocortical adenomas can be either subtle or overt. The mechanisms leading to the autonomous hypersecretion of cortisol are unknown. Objective: The objective of the study was to identify the gene expression profile associated with the autonomous and excessive cortisol secretion of adrenocortical adenomas.
    [Show full text]
  • Large G Protein Α-Subunit Xlαs Limits Clathrin-Mediated Endocytosis And
    Large G protein α-subunit XLαs limits PNAS PLUS clathrin-mediated endocytosis and regulates tissue iron levels in vivo Qing Hea, Richard Bouleyb, Zun Liua, Marc N. Weina, Yan Zhua, Jordan M. Spatza, Chia-Yu Wangb, Paola Divieti Pajevica,c, Antonius Plagged, Jodie L. Babittb, and Murat Bastepea,1 aEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; bProgram in Membrane Biology, Department of Medicine and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; cDepartment of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118; and dDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine University of Liverpool, Liverpool L69 3BX, United Kingdom Edited by Robert J. Lefkowitz, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, and approved September 28, 2017 (received for review July 19, 2017) Alterations in the activity/levels of the extralarge G protein α-sub- encoded by the GNAS complex locus, mutations of which are unit (XLαs) are implicated in various human disorders, such as peri- responsible for multiple human diseases that affect a variety of natal growth retardation. Encoded by GNAS,XLαs is partly identical organ systems (13, 14). GNAS also gives rise to a large Gsα variant to the α-subunit of the stimulatory G protein (Gsα), but the cellular termed extralarge G protein α-subunit (XLαs) (15). Derived from actions of XLαs remain poorly defined. Following an initial proteo- an upstream, paternally active promoter, XLαs uses a separate first mic screen, we identified sorting nexin-9 (SNX9) and dynamins, key exon that splices onto exons 2–13 used by Gsα.XLαsisthuspartly components of clathrin-mediated endocytosis, as binding partners identical to Gsα and comprises most functional domains of the of XLαs.
    [Show full text]
  • Progressive Osseous Heteroplasia: Diagnosis, Treatment, and Prognosis
    The Application of Clinical Genetics Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Progressive osseous heteroplasia: diagnosis, treatment, and prognosis Robert J Pignolo1–3 Abstract: Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of Girish Ramaswamy2,3 progressive ectopic ossification. Most cases of POH are caused by heterozygous inactivat- John T Fong2,3 ing mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein Eileen M Shore2–4 of adenylyl cyclase. POH is part of a spectrum of related genetic disorders, including Frederick S Kaplan1–3 Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis, that share common features of superficial ossification and association with inactivating 1Department of Medicine, mutations of GNAS. The genetics, diagnostic criteria, supporting clinical features, current 2Department of Orthopaedic Surgery, 3The Center for Research in FOP and management, and prognosis of POH are reviewed here, and emerging therapeutic strategies Related Disorders, 4Department of are discussed. Genetics, University of Pennsylvania For personal use only. Perelman School of Medicine, Keywords: progressive osseous heteroplasia, GNAS, heterotopic ossification Philadelphia, PA, USA Introduction Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progres- sive extraskeletal bone formation (Online Mendelian Inheritance in Man 166350).1 POH is clinically suspected by cutaneous ossification,
    [Show full text]
  • Dasatinib Is an Effective Treatment for Angioimmunoblastic T-Cell
    Supplemental information Dasatinib Is An Effective Treatment For Angioimmunoblastic T-Cell Lymphoma Tran B. Nguyen1+, Mamiko Sakata-Yanagimoto1,2+*, Manabu Fujisawa3, Sharna Tanzima Nuhat3, Hiroaki Miyoshi4, Yasuhito Nannya5, Koichi Hashimoto6, Kota Fukumoto3, Olivier A. Bernard7, Yusuke Kiyoki2, Kantaro Ishitsuka2, Haruka Momose2, Shinichiro Sukegawa2, Atsushi Shinagawa8, Takuya Suyama8, Yuji Sato9, Hidekazu Nishikii1,2, Naoshi Obara1,2, Manabu Kusakabe1,2, Shintaro Yanagimoto10, Seishi Ogawa5, Koichi Ohshima4, and Shigeru Chiba1,2,11* 1. Department of Hematology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. 2. Department of Hematology, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576, Japan. 3. Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. 4. Department of Pathology, Kurume University, School of Medicine, 67 Asahi, Kurume, Fukuoka 830-0011, Japan. 5. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. 6. Tsukuba Clinical Research and Development Organization (TCReDo), University of Tsukuba, 1- 1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. 7. INSERM U1170, Gustave Roussy, Université Paris-Saclay, Equipe Labellisée Ligue Nationale Contre le Cancer, Villejuif, France. 8. Department of Hematology, Hitachi General Hospital, 2-1-1 Jonan-cho, Hitachi, Ibaraki 317-0077, Japan. 9. Department of Hematology and Oncology, Tsukuba Memorial Hospital, 1187-299 Kaname, Tsukuba, Ibaraki 300-2622, Japan. 10. Division for Health Service Promotion, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113- 0033, Japan. 11. Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
    [Show full text]
  • GNAS Gene GNAS Complex Locus
    GNAS gene GNAS complex locus Normal Function The GNAS gene provides instructions for making one component, the stimulatory alpha subunit, of a protein complex called a guanine nucleotide-binding protein (G protein). Each G protein is composed of three proteins called the alpha, beta, and gamma subunits. In a process called signal transduction, G proteins trigger a complex network of signaling pathways that ultimately influence many cell functions by regulating the activity of hormones. The G protein made with the subunit produced from the GNAS gene helps stimulate the activity of an enzyme called adenylate cyclase. This enzyme is involved in controlling the production of several hormones that help regulate the activity of endocrine glands such as the thyroid, pituitary gland, ovaries and testes (gonads), and adrenal glands. Adenylate cyclase is also believed to play a key role in signaling pathways that help regulate the development of bone (osteogenesis). In this way, the enzyme helps prevent the body from producing bone tissue in the wrong place (ectopic bone). Health Conditions Related to Genetic Changes McCune-Albright syndrome At least three GNAS gene mutations have been identified in people with McCune- Albright syndrome, a disorder that affects the bones, skin, and several hormone- producing (endocrine) tissues. These mutations result in an abnormal version of the G protein that causes the adenylate cyclase enzyme to be constantly turned on ( constitutively activated). Constitutive activation of the adenylate cyclase enzyme leads to over-production of several hormones, resulting in the signs and symptoms of McCune- Albright syndrome. McCune-Albright syndrome is not inherited. The gene mutation that causes this disorder is described as somatic.
    [Show full text]