DOCSLIB.ORG

GUCA1A Mutation Causes Maculopathy in a Five-Generation Family with a Wide Spectrum of Severity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
GUCA1A Mutation Causes Maculopathy in a Five-Generation Family with a Wide Spectrum of Severity Official journal of the American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Open GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity Xue Chen, MD, PhD1,2,3, Xunlun Sheng, MD, PhD4, Wenjuan Zhuang, MD, PhD4, Xiantao Sun, MD5, Guohua Liu, MD6, Xun Shi, MD7, Guofu Huang, MD7, Yan Mei, MD7, Yingjie Li, MD7, Xinyuan Pan, MSc2, Yani Liu, MD4, Zili Li, MD4, Qingshun Zhao, PhD8, Biao Yan, PhD9 and Chen Zhao, MD, PhD1,2,3,5,10 Purpose: The aim of this study was to investigate the genetic basis Those phenotypes could not be fully rescued by exogenous wild- and pathogenic mechanism of variable maculopathies, ranging from type GUCA1A, suggesting a likely gain-of-function mechanism for mild photoreceptor degeneration to central areolar choroidal dystro- p.R120L. GUCA1A p.D100E, another mutation previously implicated phy, in a five-generation family. in cone dystrophy, also impaired the retinal pigment epithelium and photoreceptors in zebrafish, but probably via a dominant negative Methods: Clinical characterizations, whole-exome sequencing, and effect. genome-wide linkage analysis were carried out on the family. Zebraf- ish models were used to investigate the pathogenesis of GUCA1A Conclusion: We conclude that GUCA1A mutations could cause sig- mutations. nificant variability in maculopathies, including central areolar cho- roidal dystrophy, which represents a severe pattern of maculopathy. Results: A novel mutation, GUCA1A p.R120L, was identified in the The diverse pathogenic modes of GUCA1A mutations may explain family and predicted to alter the tertiary structure of guanylyl cyclase- the phenotypic diversities. activating protein 1, a photoreceptor-expressed protein encoded by the GUCA1A gene. The mutation was shown in zebrafish to cause Genet Med advance online publication 26 January 2017 significant disruptions in photoreceptors and retinal pigment epithe- Key Words: GUCA1A; maculopathy; medical genetics; lium, together with atrophies of retinal vessels and choriocapillaris. ­ophthalmology; pathogenic mechanism INTRODUCTION regulating the retinal guanylate cyclase 1 (retGC1) –medicated Inherited retinal degenerations (IRDs) include a group of cyclic guanosine monophosphate production in a calcium- diverse retinal degenerative diseases presenting both genetic sensing manner.5,6 RetGC1 is encoded by the guanylate cyclase and clinical heterogeneities. To date, according to RetNet 2D gene (GUCY2D; MIM 600179). The important roles of (https://sph.uth.edu/retnet/), 293 loci (including 256 identified GCAP1 and retGC1 in regulating hemostasis of calcium and genes) have been associated with IRDs. Among the 256 identi- cyclic guanosine monophosphate in photoreceptors have been fied genes, the guanylate cyclase activator 1A gene (GUCA1A; well addressed. MIM 600364) has been implicated in dominant cone dystro- In this study we found a novel GUCA1A mutation to be dis- phy, cone-rod dystrophy, and macular dystrophy.1–3 GUCA1A, ease causative in a five-generation family affected with variable located in 6p21.1, encodes the guanylyl cyclase-activating pro- maculopathies ranging from mild photoreceptor degeneration tein 1 (GCAP1), a photoreceptor-specific protein with more to central areolar choroidal dystrophy (CACD). CACD is a spe- expression in the inner segment/outer segment (OS) layer of cial form of IRD that mainly affects the maculae and is char- cones than rods in mammals.4 GCAP1 is a critical component acterized by a well-defined atrophic region of retinal pigment in the phototransduction cascade, which acts as a calcium sen- epithelium (RPE) and choriocapillaris at the latest stage.7–9 sor in the recovery of photoreceptors from photon capture by Before our study, mutations in two other genes, peripherin-2 The first three authors contributed equally to this work. 1Department of Ophthalmology and Vision Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; 2Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing, China; 3Key Laboratory of Myopia of State Health Ministry (Fudan University) and Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China; 4Department of Ophthalmology, Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities), Yinchuan, China; 5Department of Ophthalmology, Children’s Hospital of Zhengzhou, Zhengzhou, China; 6Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China; 7Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, China; 8MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China; 9Research Center, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; 10State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat Sen University, Guangzhou, China. Correspondence: Chen Zhao ([email protected]) or Biao Yan ([email protected]) Submitted 6 July 2016; accepted 18 November 2016; advance online publication 26 January 2017. doi:10.1038/gim.2016.217 GENETICS in MEDICINE | Volume 19 | Number 8 | August 2017 945 ORIGINAL RESEARCH ARTICLE CHEN et al | GUCA1A mutation causes variable maculopathy (PRPH2; MIM 179605) and GUCY2D, were implicated in Exome sequencing and bioinformatics analysis CACD etiology.8,10–12 We also found that diverse pathogenic Two patients, DC-IV:3 and DC-IV:13, were selected for whole- mechanisms of GUCA1A mutations might correlate with the exome sequencing using the SureSelect Human All Exon phenotypic diversity of IRDs. 50Mb Kit (Agilent Technologies, Santa Clara, CA) and the HiSeq 2000 platform (Illumina, San Diego, CA).15 Illumina MATERIALS AND METHODS base-calling software v1.7 was then applied to turn raw image Participants and clinical assessments files into 90-base-paired-end reads. Bioinformatics were sub- Our study conformed to the Declaration of Helsinki and sequently analyzed, and mutations validated.16,17 Briefly, all was prospectively reviewed and approved by the ethics com- detected variants were initially filtered against six single-nucle- mittee of Ningxia Eye Hospital. Written informed consent otide polymorphism databases, including dbSNP144 (http:// was obtained from all participants before their enrollment. hgdownload.cse.ucsc.edu/goldenPath/hg19/database/snp144. Eighteen patients and 18 unaffected family members from txt.gz), the HapMap project (ftp://ftp.ncbi.nlm.nih.gov/hap- family DC were included in the study (Figure 1). Medical map), the 1000 Genomes Project (ftp://ftp.1000genomes.ebi. records from each participant were reviewed. Routine oph- ac.uk/vol1/ftp), the YanHuang database (http://yh.genomics. thalmic examination was conducted for all participants, and org.cn/), the Exome Variant Server (http://evs.gs.washington. all patients received comprehensive ophthalmic examinations, edu/EVS/), and the Exome Aggregation Consortium database including best-corrected visual acuity, slit-lamp examination, (http://exac.broadinstitute.org/). Noncoding variants were dis- visual field test, funduscopic evaluations, and electroretino- carded, and only variants located within an annotated exon grams. Fundus autofluorescence, fundus fluorescein angiog- or within 10 base pairs on either side were analyzed further. raphy, optical coherence tomography, and electroretinography Intrafamilial cosegregation analysis and prevalence testing in were performed when possible. Another 423 unrelated Chinese the 423 unrelated controls were then conducted with the prim- controls free of maculopathy and other major ocular diseases ers detailed in Supplementary Table S1 online. were also recruited. Samples of peripheral venous blood (5 ml) were collected from each participant for genomic DNA extrac- In silico analyses tion using a QIAmp DNA Mini Blood Kit (Qiagen, Hilden, Evolutionary conservation of the mutated residues was analyzed Germany). with Vector NTI Advance 2011 (Invitrogen, Carlsbad, CA) by aligning the protein sequence of human GCAP1 (NP_000400.2) Linkage analysis with sequences of the following orthologous proteins: Pan Thirteen patients from family DC (II:11, II:13, III:7, III:14, troglodytes (ENSPTRP00000031039), Canis lupus familia- III:16, III:18, III:20, III:31, IV:3, IV:6, IV:9, IV:13, and V:3) and ris (ENSCAFP00000002385), Bos taurus (NP_776971.1), Sus four unaffected members from the same family (III:23, III:35, scrofa (ENSSSCP00000001774), Mus musculus (NP_032215.2), IV:12, and IV:18) were carefully examined and genotyped. Gallus gallus (NP_989651), and Danio rerio (NP_571945.1). Genome-wide linkage analysis was conducted in collaboration Crystal structural models of the wild-type (WT) and mutant with Genesky Biotech (Shanghai, China) using a total of 366 GCAP1 were constructed using the SWISS-MODEL online microsatellite markers spaced at about 10 cM (Weber set 6.0) server. Predicted structures were displayed by PyMol software and distributed throughout all autosomes; these markers were (version 1.5). amplified by polymerase chain reaction (PCR) using primers labeled by FAM.13,14 PCR products were appropriately pooled Plasmids construction and messenger RNA synthesis according to allele size and labeling, mixed with GeneScan-500 The open reading frame sequence of WT human GUCA1A TAMRA standard (Applied Biosystems, Foster
Load more

Recommended publications
  • Genetic Determinants Underlying Rare Diseases Identified Using Next-Generation Sequencing Technologies
    Western University Scholarship@Western Electronic Thesis and Dissertation Repository 8-2-2018 1:30 PM Genetic determinants underlying rare diseases identified using next-generation sequencing technologies Rosettia Ho The University of Western Ontario Supervisor Hegele, Robert A. The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Rosettia Ho 2018 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Medical Genetics Commons Recommended Citation Ho, Rosettia, "Genetic determinants underlying rare diseases identified using next-generation sequencing technologies" (2018). Electronic Thesis and Dissertation Repository. 5497. https://ir.lib.uwo.ca/etd/5497 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Rare disorders affect less than one in 2000 individuals, placing a huge burden on individuals, families and the health care system. Gene discovery is the starting point in understanding the molecular mechanisms underlying these diseases. The advent of next- generation sequencing has accelerated discovery of disease-causing genetic variants and is showing numerous benefits for research and medicine. I describe the application of next-generation sequencing, namely LipidSeq™ ‒ a targeted resequencing panel for the identification of dyslipidemia-associated variants ‒ and whole-exome sequencing, to identify genetic determinants of several rare diseases. Utilization of next-generation sequencing plus associated bioinformatics led to the discovery of disease-associated variants for 71 patients with lipodystrophy, two with early-onset obesity, and families with brachydactyly, cerebral atrophy, microcephaly-ichthyosis, and widow’s peak syndrome.
    [Show full text]
  • Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights Froma Highly Derived Visual Phenotype Rui Borges Universidade Do Porto - Portugal
    Nova Southeastern University NSUWorks Biology Faculty Articles Department of Biological Sciences 8-22-2019 Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights froma Highly Derived Visual Phenotype Rui Borges Universidade do Porto - Portugal Joao Fonseca Universidade do Porto - Portugal Cidalia Gomes Universidade do Porto - Portugal Warren E. Johnson Smithsonian Institution Stephen James O'Brien St. Petersburg State University - Russia; Nova Southeastern University, [email protected] See next page for additional authors Follow this and additional works at: https://nsuworks.nova.edu/cnso_bio_facarticles Part of the Biology Commons NSUWorks Citation Borges, Rui; Joao Fonseca; Cidalia Gomes; Warren E. Johnson; Stephen James O'Brien; Guojie Zhang; M. Thomas P. Gilbert; Erich D. Jarvis; and Agostinho Antunes. 2019. "Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights froma Highly Derived Visual Phenotype." Genome Biology and Evolution 11, (8): 2244-2255. doi:10.1093/gbe/evz111. This Article is brought to you for free and open access by the Department of Biological Sciences at NSUWorks. It has been accepted for inclusion in Biology Faculty Articles by an authorized administrator of NSUWorks. For more information, please contact [email protected]. Authors Rui Borges, Joao Fonseca, Cidalia Gomes, Warren E. Johnson, Stephen James O'Brien, Guojie Zhang, M. Thomas P. Gilbert, Erich D. Jarvis, and Agostinho Antunes This article is available at NSUWorks: https://nsuworks.nova.edu/cnso_bio_facarticles/982 GBE Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights from a Highly Derived Visual Downloaded from https://academic.oup.com/gbe/article-abstract/11/8/2244/5544263 by Nova Southeastern University/HPD Library user on 16 September 2019 Phenotype Rui Borges1,2,Joao~ Fonseca1,Cidalia Gomes1, Warren E.
    [Show full text]
  • Progressive Cone and Cone-Rod Dystrophies
    Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-313278 on 24 January 2019. Downloaded from Review Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy Jasdeep S Gill,1 Michalis Georgiou,1,2 Angelos Kalitzeos,1,2 Anthony T Moore,1,3 Michel Michaelides1,2 ► Additional material is ABSTRact proteins involved in photoreceptor structure, or the published online only. To view Progressive cone and cone-rod dystrophies are a clinically phototransduction cascade. please visit the journal online (http:// dx. doi. org/ 10. 1136/ and genetically heterogeneous group of inherited bjophthalmol- 2018- 313278). retinal diseases characterised by cone photoreceptor PHOTORECEPTION AND THE degeneration, which may be followed by subsequent 1 PHOTOTRANSDUCTION CASCADE UCL Institute of rod photoreceptor loss. These disorders typically present Rod photoreceptors contain rhodopsin phot- Ophthalmology, University with progressive loss of central vision, colour vision College London, London, UK opigment, whereas cone photoreceptors contain 2Moorfields Eye Hospital NHS disturbance and photophobia. Considerable progress one of three types of opsin: S-cone, M-cone or Foundation Trust, London, UK has been made in elucidating the molecular genetics L-cone opsin. Disease-causing sequence variants 3 Ophthalmology Department, and genotype–phenotype correlations associated with in the genes encoding the latter two cone opsins University of California San these dystrophies, with mutations in at least 30 genes
    [Show full text]
  • Molecular Characterization of the Interaction Between Peripherin-2 and Opsins in Rod and Cone Photoreceptors
    Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Molecular characterization of the interaction between peripherin-2 and opsins in rod and cone photoreceptors Ong Nam Phuong Nguyen aus München 2016 Erklärung Die Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Martin Biel betreut. Eidesstattliche Versicherung Die Dissertation wurde eigenständig und ohne unerlaubte Hilfsmittel erarbeitet. München, den ……………………. ………………………………………….. (Ong Nam Phuong Nguyen) Dissertation eingereicht am: 29.01.2016 1. Gutachter: Prof. Dr. Martin Biel 2. Gutachter: PD Dr. Stylianos Michalakis Mündliche Prüfung am: 24.02.2016 Table of contents Table of contents Table of contents .................................................................................................................. I 1 Introduction ............................................................................................................ 1 1.1 Anatomy of the retina ............................................................................................... 1 1.2 Anatomy of photoreceptors ...................................................................................... 2 1.3 Signaling transduction in photoreceptors .................................................................. 3 1.4 Topology and function of retinal opsins .................................................................... 5 1.5 Peripherin-2 .............................................................................................................
    [Show full text]
  • Nitrosourea Mutagenesis Causes Retinal Degeneration in Mice
    Molecular Vision 2010; 16:378-391 <http://www.molvis.org/molvis/v16/a44> © 2010 Molecular Vision Received 18 May 2009 | Accepted 1 March 2010 | Published 10 March 2010 A monogenic dominant mutation in Rom1 generated by N-ethyl-N- nitrosourea mutagenesis causes retinal degeneration in mice Hajime Sato,1 Tomohiro Suzuki,2 Kyoko Ikeda,2 Hiroshi Masuya,3 Hideki Sezutsu,4 Hideki Kaneda,2 Kimio Kobayashi,2 Ikuo Miura,2 Yasuyuki Kurihara,5 Shunji Yokokura,1 Kohji Nishida,1 Makoto Tamai,1 Yoichi Gondo,6 Tetsuo Noda,7 Shigeharu Wakana2 (The first two authors contributed equally to this work) 1Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, Ibaraki, Japan; 3Technology and Development Unit for Knowledge Base of Mouse Phenotype, RIKEN BioResource Center, Ibaraki, Japan; 4Transgenic Silkworm Research Center, National Institute of Agrobiological Sciences, Ibaraki, Japan; 5Department of Environment and National Science, Graduate School of Environment and Information Science, Yokohama National University, Yokohama, Japan; 6Mutagenesis and Genomics Team, RIKEN BioResource Center, Ibaraki, Japan; 7Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, Ibaraki, Japan Purpose: To characterize an N-ethyl-N-nitrosourea-induced dominant mouse mutant, M-1156, that exhibits progressive retinal degeneration and to investigate the pathogenesis of the retinal phenotype in the mutant. Methods: A positional candidate gene approach was used to identify the causative gene in the M-1156 mutant. Funduscopic examination, light microscopy, transmission electron microscopy, and electroretinography were performed to analyze the M-1156 phenotype. Real-time quantitative PCR, immunohistochemistry, and western blotting were also performed.
    [Show full text]
  • Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa
    Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa Stephen P. Daiger, Sara J. Bowne, and Lori S. Sullivan Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas 77030 Correspondence: [email protected] Retinitis pigmentosa (RP) has a prevalence of approximately one in 4000; 25%–30% of these cases are autosomal dominant retinitis pigmentosa (adRP). Like other forms of inherited retinal disease, adRP is exceptionally heterogeneous. Mutations in more than 25 genes are known to cause adRP,more than 1000 mutations have been reported in these genes, clinical findings are highly variable, and there is considerable overlap with other types of inherited disease. Currently, it is possible to detect disease-causing mutations in 50%–75% of adRP families in select populations. Genetic diagnosis of adRP has advantages over other forms of RP because segregation of disease in families is a useful tool for identifying and confirming potentially pathogenic variants, but there are disadvantages too. In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families. etinitis pigmentosa (RP) is an inherited dys- grams (ERGs), changes in structure imaged by Rtrophic or degenerative disease of the retina optical coherence tomography (OCT), and sub- with a prevalence of roughly one in 4000 (Haim jective changes in visual function (Fishman et al. 2002; Daiger et al. 2007).
    [Show full text]
  • Mouse Models of Human Disease. Part II: Recent Progress and Future Directions
    Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Mouse models of human disease. Part II: Recent progress and future directions Mary A. Bedell, 1 David A. Largaespada, 2 Nancy A. Jenkins, and Neal G. Copeland 3 Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201 USA The development of new methods for manipulating the the recent progress in this area. Throughout the text and mouse genome, including transgenic and embryonic tables, we have cited only the most recent papers and stem (ES) cell knockout technology, combined with refer to reviews whenever possible. Interested readers are greatly improved genetic and physical maps for mouse encouraged to read the primary papers on each model has revolutionized our ability to generate new mouse and associated disease. models of human disease. In Part I of this review (Bedell et al., this issue), we described in detail the various tech- Disorders of neural crest derivatives niques and genetic resources that have facilitated mouse model development. In Part II of this review we highlight Cells from the neural crest differentiate into many dif- some of the recent progress that has been made in mouse ferent cell types including melanocytes of the skin and model development and discuss areas where these inner ear, neuronal and glial components of the periph- mouse models are likely to contribute in the future. We eral nervous system, neuroendocrine cells of the adrenal have focused in part II only on those models where the medulla and thyroid, and cartilaginous and membranous homologous gene is mutated in both the human and bones of the skull.
    [Show full text]
  • Novel Insights Into the Pathophysiology of Peripherin-2 Mutations in Rod and Cone Photoreceptors
    Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Novel Insights into the Pathophysiology of Peripherin-2 Mutations in Rod and Cone Photoreceptors Sybille Böhm aus Schäßburg, Rumänien 2018 Erklärung Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Martin Biel betreut. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, den 12.10.2018 _______________________ (Sybille Böhm) Dissertation eingereicht am 12.10.2018 1. Gutachter: Prof. Dr. Martin Biel 2. Gutachter: PD Dr. Stylianos Michalakis Mündliche Prüfung am 18.12.2018 Table of contents 3 Table of contents 1 Preface .........................................................................................................................7 2 Introduction .................................................................................................................8 2.1 Anatomy of the retina .................................................................................................... 8 2.2 Anatomy of photoreceptors .......................................................................................... 9 2.3 Inherited retinal diseases ............................................................................................ 10 2.3.1 Retinitis pigmentosa ....................................................................................................... 10 2.4 Peripherin-2 .................................................................................................................
    [Show full text]
  • Molecular Diagnostic Testing by Eyegene: Analysis of Patients with Hereditary Retinal Dystrophy Phenotypes Involving Central Vision Loss
    Genetics Molecular Diagnostic Testing by eyeGENE: Analysis of Patients With Hereditary Retinal Dystrophy Phenotypes Involving Central Vision Loss Akhila Alapati,1 Kerry Goetz,2 John Suk,1 Mili Navani,1 Amani Al-Tarouti,3 Thiran Jayasundera,3 Santa J. Tumminia,4 Pauline Lee,1 and Radha Ayyagari1 1Shiley Eye Center, University of California-San Diego, La Jolla, California, United States 2Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States 3W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States 4Office of the Director, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States Correspondence: Radha Ayyagari, PURPOSE. To analyze the genetic test results of probands referred to eyeGENE with a diagnosis Shiley Eye Center, Jacobs Retina of hereditary maculopathy. Center,Room206,Universityof California-San Diego, 9415 Campus METHODS. Patients with Best macular dystrophy (BMD), Doyne honeycomb retinal dystrophy Point Drive, San Diego, CA 92093, (DHRD), Sorsby fundus dystrophy (SFD), or late-onset retinal degeneration (LORD) were USA; screened for mutations in BEST1, EFEMP1, TIMP3, and CTRP5, respectively. Patients with [email protected]. pattern dystrophy (PD) were screened for mutations in PRPH2, BEST1, ELOVL4, CTRP5, and Submitted: March 14, 2014 ABCA4; patients with cone-rod dystrophy (CRD) were screened for mutations in CRX, Accepted: July 18, 2014 ABCA4, PRPH2, ELOVL4, and the c.2513G>A p.Arg838His variant in GUCY2D. Mutation analysis was performed by dideoxy sequencing. Impact of novel variants was evaluated using Citation: Alapati A, Goetz K, Suk J, et al. Molecular diagnostic testing by the computational tool PolyPhen.
    [Show full text]
  • Retinal Dystrophies and Variants in PRPH2
    A RQUIVOS B RASILEIROS DE LETTERS Retinal dystrophies and variants in PRPH2 Distrofias retinianas e variantes em PRPH2 Mariana Matioli da Palma1,2, Daniel Martin1, Mariana Vallim Salles2,3, Fabiana Louise Teixeira Motta2,3, Suel Abujamra1, Juliana Maria Ferraz Sallum2,3 1. Instituto Suel Abujamra, São Paulo, SP, Brazil. 2. Universidade Federal de São Paulo, São Paulo, SP, Brazil. 3. Instituto de Genética Ocular, São Paulo, SP, Brazil. ABSTRACT | This report presents three patients diagnosed degeneration in rats(1). The peripherin-2 protein codified with macular dystrophies with variants in PRPH2. Peripherin-2, for this gene is essential in the morphogenesis of the the protein of this gene, is important in the morphogenesis and photoreceptor outer segment composed of parallel, stabilization of the photoreceptor outer segment. Peripherin-2 closely packed bilaminar discs in the plasma membrane. deficiencies cause cellular apoptosis. Moreover, pathogenic variants Each disc contains a rim and a lamella. The rim surroun- in PRPH2 are associated with various diseases, such as pattern, butterfly-shaped pattern, central areolar, adult-onset vitelliform ds the extremity of the disc and maintains the flattened macular, and cone-rod dystrophies as well as retinitis pigmentosa, morphology; the lamella is where phototransduction occurs. retinitis punctata albescens, Leber congenital amaurosis, fundus Vision is affected when this structure is altered(2,3). flavimaculatus, and Stargardt disease. Peripherin-2 is a transmembrane glycoprotein that Keywords: Retinal degeneration; Genotyping techniques; is intrinsic to both the curvature formation of each disc Vitelliform macular dystrophy; Retinitis pigmentosa; Genetics and the flattened surface morphology. Deficiency of this protein results in cellular disorganization and cellular RESUMO | Este relato apresenta três pacientes com diagnóstico apoptosis activation via unknown mechanisms(2,3).
    [Show full text]
  • Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss
    cells Review Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss 1, 1, 1 1,2,3 1 Gayle B. Collin y, Navdeep Gogna y, Bo Chang , Nattaya Damkham , Jai Pinkney , Lillian F. Hyde 1, Lisa Stone 1 , Jürgen K. Naggert 1 , Patsy M. Nishina 1,* and Mark P. Krebs 1,* 1 The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; [email protected] (G.B.C.); [email protected] (N.G.); [email protected] (B.C.); [email protected] (N.D.); [email protected] (J.P.); [email protected] (L.F.H.); [email protected] (L.S.); [email protected] (J.K.N.) 2 Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand 3 Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand * Correspondence: [email protected] (P.M.N.); [email protected] (M.P.K.); Tel.: +1-207-2886-383 (P.M.N.); +1-207-2886-000 (M.P.K.) These authors contributed equally to this work. y Received: 29 February 2020; Accepted: 7 April 2020; Published: 10 April 2020 Abstract: Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated.
    [Show full text]
  • PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation
    G C A T T A C G G C A T genes Article PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation Rosa M. Coco-Martin 1,2,*, Hortensia T. Sanchez-Tocino 3 , Carmen Desco 4 , Ricardo Usategui-Martín 1 and Juan J. Tellería 1 1 Instituto Universitario de Oftalmobiologia Aplicada, Universidad de Valladolid, 47011 Valladolid, Spain; [email protected] (R.U.-M.); [email protected] (J.J.T.) 2 Red Temática de Investigación Cooperativa en Salud de Oftalmologia (Oftared), Instituto de Salud Carlos III, 28029 Madrid, Spain 3 Department of Ophthalmology, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain; [email protected] 4 Fisabio Oftalmologia Medica, 46035 Valencia, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-983-423-559 (ext. 4738) Received: 8 June 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: Over 175 pathogenic mutations in the Peripherin-2 (PRPH2) gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct PRPH2 gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, in a patient with adult-onset vitelliform macular dystrophy (AVMD). One family with the p.Arg46Ter mutation presented with the already described AVMD phenotype, but another family presented with the same mutation and two heterozygous pathogenic mutations (p.Leu2027Phe and p.Gly1977Ser) in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene that cause extensive chorioretinal atrophy (ECA), which could be a blended phenotype. The p.Lys154del PRPH2 gene mutation associated with the p.Arg2030Glu mutation in the ABCA4 gene was found in a patient with multifocal pattern dystrophy simulating fundus flavimaculatus (PDsFF), for whom we considered ABCA4 as a possible modifying gene.
    [Show full text]