DOCSLIB.ORG

The Familial Dementia Gene Revisited: a Missense Mutation Revealed By

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Familial Dementia Gene Revisited: a Missense Mutation Revealed By Human Molecular Genetics, 2014, Vol. 23, No. 2 491–501 doi:10.1093/hmg/ddt439 Advance Access published on September 10, 2013 The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family Isabelle Audo1,2,3,4,5,∗, Kinga Bujakowska1,2,3, Elise Orhan1,2,3, Said El Shamieh1,2,3, Florian Downloaded from https://academic.oup.com/hmg/article/23/2/491/663466 by guest on 01 October 2021 Sennlaub1,2,3, Xavier Guillonneau1,2,3, Aline Antonio1,2,3, Christelle Michiels1,2,3, Marie-Elise Lancelot1,2,3, Melanie Letexier6, Jean-Paul Saraiva6, Hoan Nguyen7, Tien D. Luu7, Thierry Le´veillard1,2,3, Olivier Poch7,He´le`ne Dollfus8,9, Michel Paques1,2,3,4, Olivier Goureau1,2,3, Saddek Mohand-Saı¨d1,2,3,4, Shomi S. Bhattacharya1,2,3,5,10, Jose´-Alain Sahel1,2,3,4,11,12 and Christina Zeitz1,2,3 1INSERM, U968, Paris F-75012, France, 2CNRS, UMR_7210, Paris F-75012, France, 3Department of Genetics, Institut de la Vision, UPMC Univ Paris 06, UMR_S 968, Paris F-75012, France, 4Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris F-75012, France, 5Department of Genetics, UCL-Institute of Ophthalmology, 11–43 Bath Street, London EC1V 9EL, UK, 6IntegraGen SA, Genopole CAMPUS 1 bat G8, Evry FR- 91030, France, 7Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire, Illkirch Cedex 67404, France, 8Centre de Re´fe´rence pour les Affections Rares en Ge´ne´tique Ophtalmologique, Hoˆpitaux Universitaires de Strasbourg, Strasbourg, France, 9Laboratoire de ge´ne´tique me´dicale, Universite´ de Strasbourg, UMR-S INSERM U1112, Strasbourg, France, 10Andalusian Centre for Molecular Biology and Regenerative Medicine (CABIMER), Isla de Cartuja, Seville, Spain, 11Fondation Ophtalmologique Adolphe de Rothschild, Paris, France and 12Acade´mie des Sciences–Institut de France, Paris 75006, France Received July 18, 2013; Revised and Accepted September 4, 2013 Inherited retinal diseases are a group of clinically and genetically heterogeneous disorders for which a signifi- cant number of cases remain genetically unresolved. Increasing knowledge on underlying pathogenic mechan- isms with precise phenotype–genotype correlation is, however, critical for establishing novel therapeutic interventions for these yet incurable neurodegenerative conditions. We report phenotypic and genetic charac- terization of a large family presenting an unusual autosomal dominant retinal dystrophy. Phenotypic character- ization revealed a retinopathy dominated by inner retinal dysfunction and ganglion cell abnormalities. Whole- exome sequencing identified a missense variant (c.782A>C, p.Glu261Ala) in ITM2B coding for Integral Membrane Protein 2B, which co-segregates with the disease in this large family and lies within the 24.6 Mb inter- val identified by microsatellite haplotyping. The physiological role of ITM2B remains unclear and has never been investigated in the retina. RNA in situ hybridization reveals Itm2b mRNA in inner nuclear and ganglion cell layers within the retina, with immunostaining demonstrating the presence of the corresponding protein in the same layers. Furthermore, ITM2B in the retina co-localizes with its known interacting partner in cerebral tissue, the ∗To whom correspondence should be addressed at: Department of Genetics, Institut de la Vision, 17, Rue Moreau, Paris 75012, France. Tel: +33 153462542; Fax: +33 153462602; Email: [email protected] # The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] 492 Human Molecular Genetics, 2014, Vol. 23, No. 2 amyloid b precursor protein, critical in Alzheimer disease physiopathology. Interestingly, two distinct ITM2B mutations, both resulting in a longer protein product, had already been reported in two large autosomal domin- ant families with Alzheimer-like dementia but never in subjects with isolated retinal diseases. These findings should better define pathogenic mechanism(s) associated with ITM2B mutations underlying dementia or retinal disease and add a new candidate to the list of genes involved in inherited retinal dystrophies. INTRODUCTION RESULTS Inherited retinal dystrophies are a heterogeneous group of Clinical characterization disorders including stationary conditions such as congenital The reported family includes at least 14 affected family members stationary night blindness (CSNB) characterized by post- spanning three generations, with two deceased, suffering Downloaded from https://academic.oup.com/hmg/article/23/2/491/663466 by guest on 01 October 2021 phototransduction dysfunction or degenerative processes such from visual symptoms segregating as a dominant trait (Fig. 1, as rod–cone and cone–rod dystrophies. This clinical heterogen- proband with a single arrow). Eleven affected and eight unaf- eity is mirrored by genetic heterogeneity (https://sph.uth.edu/ fected subjects were available for genetic testing. Detailed clin- Retnet/, last accessed date on September 16, 2013). Despite ical examination was performed on affected family members the increasing number of identified genes recognized for their ranging in age from 46 to 73 years (average 54) (Table 1). role in retinal physiology and pathology, the underlying Onset of symptoms appeared between 25 and 40 years genetic defect(s) remains unknown in a number of cases. Increas- (average 36). Light sensitivity was the first sign, reported by ing knowledge in pathogenic mechanisms and their associated all subjects, followed by progressive loss of central vision. phenotype–genotype correlation is de facto critical for a better Visual acuity varied from 20/25 to 20/400 (average 20/50). understanding of these heterogeneous disorders, even for rare Visual fields showed decreased central retinal sensitivity with subgroups. It may not only provide important insights into the preservation of peripheral visual field. Fundus examination, complexity of retinal physiology or neurophysiology in general fundus autofluorescence imaging and spectral domain optical but also help for accurate counselling and, moreover, for the es- coherence tomography (SD-OCT) revealed macular changes tablishment of innovative therapeutic interventions in these yet associated with optic disc pallor, hyper-reflectivity of ganglion incurable conditions. Recently, techniques of next-generation se- cell and nerve fibre layers (Fig. 2A) with loss of optic nerve quencing (NGS) have proved their efficiency to increase chances fibres (Fig. 2B). Full-field electroretinogram (Fig. 2C) showed of deciphering unknown genetic defect in this context (1). inner retinal dysfunction in all cases: all affected subjects dis- We applied these techniques to decipher the underlying gene played an absent or very reduced b-wave in response to a dim defect in a large dominant pedigree with 14 members affected by flash of 0.01 cd s m22 under dark-adapted (scotopic) conditions; a clinically novel retinal dystrophy dominated by inner retinal stimulation with a bright flash (3 and 12 0.01 cd s m22) under dysfunction and ganglion cell abnormalities. Applying whole- scotopic conditions revealed a normal a-wave, reflecting exome sequencing and subsequent haplotype analysis, we iden- normal photoreceptor function, dominated under dark adapta- tified a missense mutation in ITM2B, encoding Integral Mem- tion by rod function, but a severely reduced b-wave, reflecting brane Protein 2B, which co-segregates with the disease, and post-receptoral dysfunction with the typical electronegative further investigated expression of this gene in the retina. waveform. Oscillatory potentials, originating at the inner retinal Figure 1. Family pedigree revealing autosomal dominant segregation of the disease. Affected individuals are presented with filled symbols, unaffected with white symbols;squaresymbolsrepresentmaleandroundsymbols,female;deceasedindividualsare presentedwitha slash;subjectswho underwent ophthalmicevaluationin our centre are marked with an asterisk; mutation segregation is shown on the pedigree as ‘[¼];[¼]’ carrying both normal allele and ‘[M];[¼]’ heterozygous for the mutant change; the proband IV.27 is marked with a double black arrow and his DNA sample was included in whole-exome sequencing; other subjects includedin whole-exome sequencing are marked with arrows (i.e. IV.1 and IV.12). Table 1. Clinical characteristics of affected family members Patient Age at Age of onset Sex Symptoms BCVA Colour vision Kinetic visual field Fundus examination FAF SD-OCT the time OD/OS of testing refraction III.13 73 Around 40 F Mild photophobia 20/100; 20/250 OD normal Relative central scotoma Temporal optic disc Hyper-autofluorescent ring Hyper-reflectivity within Decreased vision 21.75 (21.75) OS mild tritanopia within 10 central pallor; mild around the macular region; the foveal ONL; small Downloaded fromhttps://academic.oup.com/hmg/article/23/2/491/663466bygueston01October2021 958 degrees with normal retinal vessel hypo-autofluorescence drusenoid changes in 23.75 (20.5) 708 peripheral isopter narrowing; foveal within the ring with subtle the foveal region; changes foveal hyper-reflectivity of hyper-autofluorescence the inner retina III.15 72 Around 40 F Mild photophobia 20/250; 20/400 OD and OS mild Relative central scotoma Pale optic disc; mild Hyper-autofluorescent ring Hyper-reflectivity within Decreased vision +1.25 (21.75) deuteranopia within 20 central retinal vessel around the macular region;
Load more

Recommended publications
  • Prioritization and Evaluation of Depression Candidate Genes by Combining Multidimensional Data Resources
    Prioritization and Evaluation of Depression Candidate Genes by Combining Multidimensional Data Resources Chung-Feng Kao1, Yu-Sheng Fang2, Zhongming Zhao3, Po-Hsiu Kuo1,2,4* 1 Department of Public Health and Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan, 2 Institute of Clinical Medicine, School of Medicine, National Cheng-Kung University, Tainan, Taiwan, 3 Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America, 4 Research Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan Abstract Background: Large scale and individual genetic studies have suggested numerous susceptible genes for depression in the past decade without conclusive results. There is a strong need to review and integrate multi-dimensional data for follow up validation. The present study aimed to apply prioritization procedures to build-up an evidence-based candidate genes dataset for depression. Methods: Depression candidate genes were collected in human and animal studies across various data resources. Each gene was scored according to its magnitude of evidence related to depression and was multiplied by a source-specific weight to form a combined score measure. All genes were evaluated through a prioritization system to obtain an optimal weight matrix to rank their relative importance with depression using the combined scores. The resulting candidate gene list for depression (DEPgenes) was further evaluated by a genome-wide association (GWA) dataset and microarray gene expression in human tissues. Results: A total of 5,055 candidate genes (4,850 genes from human and 387 genes from animal studies with 182 being overlapped) were included from seven data sources.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Evidence for Differential Alternative Splicing in Blood of Young Boys With
    Stamova et al. Molecular Autism 2013, 4:30 http://www.molecularautism.com/content/4/1/30 RESEARCH Open Access Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders Boryana S Stamova1,2,5*, Yingfang Tian1,2,4, Christine W Nordahl1,3, Mark D Shen1,3, Sally Rogers1,3, David G Amaral1,3 and Frank R Sharp1,2 Abstract Background: Since RNA expression differences have been reported in autism spectrum disorder (ASD) for blood and brain, and differential alternative splicing (DAS) has been reported in ASD brains, we determined if there was DAS in blood mRNA of ASD subjects compared to typically developing (TD) controls, as well as in ASD subgroups related to cerebral volume. Methods: RNA from blood was processed on whole genome exon arrays for 2-4–year-old ASD and TD boys. An ANCOVA with age and batch as covariates was used to predict DAS for ALL ASD (n=30), ASD with normal total cerebral volumes (NTCV), and ASD with large total cerebral volumes (LTCV) compared to TD controls (n=20). Results: A total of 53 genes were predicted to have DAS for ALL ASD versus TD, 169 genes for ASD_NTCV versus TD, 1 gene for ASD_LTCV versus TD, and 27 genes for ASD_LTCV versus ASD_NTCV. These differences were significant at P <0.05 after false discovery rate corrections for multiple comparisons (FDR <5% false positives). A number of the genes predicted to have DAS in ASD are known to regulate DAS (SFPQ, SRPK1, SRSF11, SRSF2IP, FUS, LSM14A). In addition, a number of genes with predicted DAS are involved in pathways implicated in previous ASD studies, such as ROS monocyte/macrophage, Natural Killer Cell, mTOR, and NGF signaling.
    [Show full text]
  • Recessive Mutations of the Gene TRPM1 Abrogate on Bipolar Cell Function and Cause Complete Congenital Stationary Night Blindness in Humans
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT Recessive Mutations of the Gene TRPM1 Abrogate ON Bipolar Cell Function and Cause Complete Congenital Stationary Night Blindness in Humans Zheng Li,1 Panagiotis I. Sergouniotis,1 Michel Michaelides,1,2 Donna S. Mackay,1 Genevieve A. Wright,2 Sophie Devery,2 Anthony T. Moore,1,2 Graham E. Holder,1,2 Anthony G. Robson,1,2 and Andrew R. Webster1,2,* Complete congenital stationary night blindness (cCSNB) is associated with loss of function of rod and cone ON bipolar cells in the mammalian retina. In humans, mutations in NYX and GRM6 have been shown to cause the condition. Through the analysis of a consan- guineous family and screening of nine additional pedigrees, we have identified three families with recessive mutations in the gene TRPM1 encoding transient receptor potential cation channel, subfamily M, member 1, also known as melastatin. A number of other variants of unknown significance were found. All patients had myopia, reduced central vision, nystagmus, and electroretinographic evidence of ON bipolar cell dysfunction. None had abnormalities of skin pigmentation, although other skin conditions were reported. RNA derived from human retina and skin was analyzed and alternate 50 exons were determined. The most 50 exon is likely to harbor an initiation codon, and the protein sequence is highly conserved across vertebrate species. These findings suggest an important role of this specific cation channel for the normal function of ON bipolar cells in the human retina. Congenital stationary night blindness (CSNB) is a group of of the gene encoding transient receptor potential cation genetically determined, nondegenerative disorders of the channel, subfamily M, member 1 (TRPM1 [MIM *603576]) retina associated with lifelong deficient vision in the dark has been discovered in the skin and retina of horses homo- and often nystagmus and myopia.
    [Show full text]
  • BRI2 (Itm2b) Inhibits A␤ Deposition in Vivo
    6030 • The Journal of Neuroscience, June 4, 2008 • 28(23):6030–6036 Neurobiology of Disease BRI2 (ITM2b) Inhibits A␤ Deposition In Vivo Jungsu Kim,1 Victor M. Miller,1 Yona Levites,1 Karen Jansen West,1 Craig W. Zwizinski,1 Brenda D. Moore,1 Fredrick J. Troendle,1 Maralyssa Bann,1 Christophe Verbeeck,1 Robert W. Price,1 Lisa Smithson,1 Leilani Sonoda,1 Kayleigh Wagg,1 Vijayaraghavan Rangachari,1 Fanggeng Zou,1 Steven G. Younkin,1 Neill Graff-Radford,2 Dennis Dickson,1 Terrone Rosenberry,1 and Todd E. Golde1 Departments of 1Neuroscience and 2Neurology, Mayo Clinic College of Medicine, Mayo Clinic Jacksonville, Jacksonville, Florida 32224 AnalysesofthebiologiceffectsofmutationsintheBRI2(ITM2b)andtheamyloid␤precursorprotein(APP)genessupportthehypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer’s disease (AD) is associatedwithneurodegeneration.WehaveusedsomaticbraintransgenictechnologytoexpresstheBRI2andBRI2-A␤1–40transgenes in APP mouse models. Expression of BRI2-A␤1–40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral A␤ deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits A␤ aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of A␤ deposition in vivo. Key words: BRI2; ITM2b; amyloid ␤ protein; Alzheimer’s disease; somatic brain transgenesis; adeno-associated virus Introduction pathological and clinical similarities between FBD, FDD, and Familial British and Danish dementias (FBD and FDD, respec- Alzheimer’s disease (AD).
    [Show full text]
  • Cerebral Amyloidosis, Amyloid Angiopathy, and Their Relationship to Stroke and Dementia
    65 Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia ∗ Jorge Ghiso and Blas Frangione β-pleated sheet structure, the conformation responsi- Department of Pathology, New York University School ble for their physicochemical properties and tinctoreal of Medicine, New York, NY, USA characteristics. So far, 20 different proteins have been identified as subunits of amyloid fibrils [56,57,60 (for review and nomenclature)]. Although collectively they Cerebral amyloid angiopathy (CAA) is the common term are products of normal genes, several amyloid precur- used to define the deposition of amyloid in the walls of sors contain abnormal amino acid substitutions that can medium- and small-size leptomeningeal and cortical arteries, arterioles and, less frequently, capillaries and veins. CAA impose an unusual potential for self-aggregation. In- is an important cause of cerebral hemorrhages although it creased levels of amyloid precursors, either in the cir- may also lead to ischemic infarction and dementia. It is a culation or locally at sites of deposition, are usually the feature commonly associated with normal aging, Alzheimer result of overexpression, defective clearance, or both. disease (AD), Down syndrome (DS), and Sporadic Cerebral Of all the amyloid proteins identified, less than half are Amyloid Angiopathy. Familial conditions in which amyloid known to cause amyloid deposition in the central ner- is chiefly deposited as CAA include hereditary cerebral hem- vous system (CNS), which in turn results in cognitive orrhage with amyloidosis of Icelandic type (HCHWA-I), fa- decline, dementia, stroke, cerebellar and extrapyrami- milial CAA related to Aβ variants, including hereditary cere- dal signs, or a combination of them.
    [Show full text]
  • Transcriptome, Spliceosome and Editome Expression Patterns of The
    International Journal of Molecular Sciences Article Transcriptome, Spliceosome and Editome Expression Patterns of the Porcine Endometrium in Response to a Single Subclinical Dose of Salmonella Enteritidis Lipopolysaccharide Lukasz Paukszto 1, Anita Mikolajczyk 2, Jan P. Jastrzebski 1,3 , Marta Majewska 4 , Kamil Dobrzyn 5, Marta Kiezun 5 , Nina Smolinska 5 and Tadeusz Kaminski 5,* 1 Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland; [email protected] (L.P.); [email protected] (J.P.J.) 2 Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Warszawska 30, 10-082 Olsztyn, Poland; [email protected] 3 Bioinformatics Core Facility, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str 1A/113, 10-719 Olsztyn, Poland 4 Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Warszawska Str 30, 10-082 Olsztyn, Poland; [email protected] 5 Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland; [email protected] (K.D.); [email protected] (M.K.); [email protected] (N.S.) * Correspondence: [email protected]; Tel.: +48-89-523-44-20 Received: 15 May 2020; Accepted: 12 June 2020; Published: 13 June 2020 Abstract: Endometrial infections at a young age can lead to fertility issues in adulthood. Bacterial endotoxins, such as lipopolysaccharide (LPS), can participate in long-term molecular changes even at low concentrations.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • CPTC-CDK1-1 (CAB079974) Immunohistochemistry
    CPTC-CDK1-1 (CAB079974) Uniprot ID: P06493 Protein name: CDK1_HUMAN Full name: Cyclin-dependent kinase 1 Tissue specificity: Isoform 2 is found in breast cancer tissues. Function: Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins. Required in higher cells for entry into S-phase and mitosis. Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl-xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CENPA, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, TPPP, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SAMHD1, SIRT2 and RUNX2. CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs. Essential for early stages of embryonic development. During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation. Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis.
    [Show full text]
  • And SPP-Like Proteases☆
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1828 (2013) 2828–2839 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamem Review Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases☆ Matthias Voss a, Bernd Schröder c, Regina Fluhrer a,b,⁎ a Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Schillerstr. 44, 80336 Munich, Germany b DZNE — German Center for Neurodegenerative Diseases, Munich, Schillerstr. 44, 80336 Munich, Germany c Biochemical Institute, Christian-Albrechts-University Kiel, Olshausenstrasse 40, 24118 Kiel, Germany article info abstract Article history: Signal peptide peptidase (SPP) and the homologous SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and Received 27 December 2012 SPPL3 belong to the family of GxGD intramembrane proteases. SPP/SPPLs selectively cleave transmembrane Received in revised form 25 March 2013 domains in type II orientation and do not require additional co-factors for proteolytic activity. Orthologues of Accepted 29 March 2013 SPP and SPPLs have been identified in other vertebrates, plants, and eukaryotes. In line with their diverse subcellular localisations ranging from the ER (SPP, SPPL2c), the Golgi (SPPL3), the plasma membrane Keywords: (SPPL2b) to lysosomes/late endosomes (SPPL2a), the different members of the SPP/SPPL family seem to Regulated intramembrane proteolysis fi Intramembrane-cleaving proteases exhibit distinct functions. Here, we review the substrates of these proteases identi ed to date as well as GxGD proteases the current state of knowledge about the physiological implications of these proteolytic events as deduced Signal peptide peptidase from in vivo studies.
    [Show full text]
  • Two Novel NYX Gene Mutations in the Chinese Families with X-Linked
    www.nature.com/scientificreports OPEN Two Novel NYX Gene Mutations in the Chinese Families with X-linked Congenital Stationary Night Received: 24 November 2014 Accepted: 30 March 2015 Blindness Published: 03 August 2015 Shuzhen Dai1,2,*, Ming Ying2,3,*, Kai Wang2,3, Liming Wang2,3, Ruifang Han2,3, Peng Hao2,3 & Ningdong Li2,3 Mutations in NYX and CACNA1F gene are responsible for the X-linked congenital stationary night blindness (CSNB). In this study, we described the clinical characters of the two Chinese families with X-linked CSNB and detected two novel mutations of c. 371_377delGCTACCT and c.214A>C in the NYX gene by direct sequencing. These two mutations would expand the mutation spectrum of NYX. Our study would be helpful for further studying molecular pathogenesis of CSNB. Congenital stationary night blindness (CSNB) is a group of clinically and genetically heterogeneous reti- nal disorders characterized by night blindness, decreased visual acuity, and a reduced or absent b-wave in the electroretinogram (ERG)1. Other clinical features of CSNB may include variable degrees of myopia, a nearly normal fundus appearance, nystagmus and strabismus. Two subgroups of CSNB can be classi- fied by ERG into the “complete form” (or type 1 CSNB), and “incomplete form” (or type 2 CSNB)2. The complete form is characterized by absence of rod b-wave and oscillatory potentials due to complete loss of the rod pathway function, whereas the incomplete form shows a reduced rod b-wave, cone a-wave, and 30-Hz flicker ERG response caused by impaired rod and cone pathway function3. CSNB may be inherited as an autosomal dominant, autosomal recessive and X-linked inheritance mode.
    [Show full text]
  • Unbiased RNA-Seq-Driven Identification and Validation Of
    Dai et al. BMC Genomics (2021) 22:27 https://doi.org/10.1186/s12864-020-07318-y RESEARCH ARTICLE Open Access Unbiased RNA-Seq-driven identification and validation of reference genes for quantitative RT-PCR analyses of pooled cancer exosomes Yao Dai1, Yumeng Cao1, Jens Köhler2, Aiping Lu1, Shaohua Xu1* and Haiyun Wang1* Abstract Background: Exosomes are extracellular vesicles (EVs) derived from endocytic compartments of eukaryotic cells which contain various biomolecules like mRNAs or miRNAs. Exosomes influence the biologic behaviour and progression of malignancies and are promising candidates as non-invasive diagnostic biomarkers or as targets for therapeutic interventions. Usually, quantitative real-time polymerase chain reaction (qRT-PCR) is used to assess gene expression in cancer exosomes, however, the ideal reference genes for normalization yet remain to be identified. Results: In this study, we performed an unbiased analysis of high-throughput mRNA and miRNA-sequencing data from exosomes of patients with various cancer types and identify candidate reference genes and miRNAs in cancer exosomes. The expression stability of these candidate reference genes was evaluated by the coefficient of variation “CV” and the average expression stability value “M”. We subsequently validated these candidate reference genes in exosomes from an independent cohort of ovarian cancer patients and healthy control individuals by qRT-PCR. Conclusions: Our study identifies OAZ1 and hsa-miR-6835-3p as the most reliable individual reference genes for mRNA and miRNA quantification, respectively. For superior accuracy, we recommend the use of a combination of reference genes - OAZ1/SERF2/MPP1 for mRNA and hsa-miR-6835-3p/hsa-miR-4468-3p for miRNA analyses.
    [Show full text]