DOCSLIB.ORG

Autosomal Dominant Macular Degeneration Associated with 208Delg Mutation in the FSCN2 Gene

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Autosomal Dominant Macular Degeneration Associated with 208Delg Mutation in the FSCN2 Gene OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: EDWIN M. STONE, MD, PhD Autosomal Dominant Macular Degeneration Associated With 208delG Mutation in the FSCN2 Gene Yuko Wada, MD; Toshiaki Abe, MD; Toshitaka Itabashi, MD; Hajime Sato, MD; Miyuki Kawamura, MD; Makoto Tamai, MD Objective: To assess the clinical and genetic character- different phenotypes, autosomal dominant retinitis pig- istics of 2 Japanese families with autosomal dominant mentosa and ADMD. macular degeneration (ADMD) associated with a 208delG mutation in the retinal fascin (FSCN2) gene. Conclusions: The 208delG mutation in the FSCN2 gene produces not only autosomal dominant retinitis pigmen- Design: Case reports with clinical findings and results tosa but also ADMD in the Japanese population. This mu- of fluorescein angiography, electroretinography, ki- tation is relatively common in Japanese patients with au- netic visual field testing, and DNA analysis. tosomal dominant retinal degeneration and showed clinical variability. Setting: University medical center. Clinical Relevance: Autosomal dominant retinitis pig- Results: The 208delG mutation in the FSCN2 gene was mentosa and ADMD can be caused by the same 208delG identified in 14 members of 4 Japanese families with au- mutation. We suggest that mutations in the FSCN2 gene tosomal dominant retinitis pigmentosa and in 5 mem- can lead to a spectrum of phenotypes. bers of 2 Japanese families with ADMD. The character- istic features associated with this mutation led to 2 Arch Ophthalmol. 2003;121:1613-1620 ACULAR DEGENERATION patients with ADRP (14 patients from 4 un- (MD) can have a domi- related families) have the identical 208delG nant or recessive in- mutation in the FSCN2 gene. FSCN2, a can- heritance pattern and didate gene for ADRP, is located on chro- shows clinical and ge- mosome 17q25 and plays an important role Mnetic heterogeneity. To date, 4 loci and 6 in photoreceptor disc formation. The clini- candidate genes for MD have been re- cal characteristics of the 14 patients from ported, and 10 loci and 28 candidate genes 4 families with the 208delG mutation were for retinitis pigmentosa (RP) have been those of typical RP.14 identified.1 Among these candidate genes, However, 1 patient had an atrophic the peripherin/RDS gene causes autoso- MD in addition to the pigmentary retinal de- mal dominant retinitis pigmentosa (ADRP) generation. This finding suggested the pos- and autosomal dominant macular degen- sibility that mutations in the FSCN2 gene eration (ADMD). Therefore, it was re- were related to not only ADRP but also ported that the Arg172Trp,2-4 Tyr258Stop,5 ADMD. Thereafter, 148 patients from un- and Gly167Asp6 mutations cause ADMD related families with ADRP and 54 pa- and that the Trp179Arg,7 Cys165Thr,8 tients from unrelated families with cone- Phe211Leu,8 and Asn244Lys9 mutations rod dystrophy or MD were screened to cause ADRP. These reports suggested that search for mutations in the FSCN2 gene. other candidate genes for RP caused other Fourteen patients from 4 unrelated fami- phenotypes, such as MD. lies with ADRP and 5 patients from 2 un- From the Department of In 2001, it was first reported that the related families with ADMD had the iden- Ophthalmology, Tohoku 12 University School of Medicine, human retinal fascin gene (FSCN2) was one tical 208delG mutation in the FSCN2 gene. Sendai, Japan. The authors of the causative genes for Japanese We describe herein the ocular findings as- have no relevant financial patients with ADRP. This and other sociated with the 208delG mutation in 2 of interest in this article. studies10-14 disclosed that about 3.0% of the these Japanese families with ADMD. (REPRINTED) ARCH OPHTHALMOL / VOL 121, NOV 2003 WWW.ARCHOPHTHALMOL.COM 1613 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Family 1 Family 2 T A CCT G A C A G C T G A 12 I 1 2 I Normal Allele 12 1 X X II 2 II +/+ M/+ 12 34XX5 XXX III 1 23 M/+ +/+ III M/+ +/+ M/+ 12XX 3 IV Deletion G M/+ +/+ 1 V T A CCT– A C A G C T G A Figure 1. Pedigrees of 2 Japanese families with macular degeneration Mutant Allele associated with the 208delG mutation in the FSCN2 gene showing affected (solid symbols) and unaffected (open symbols) members. Squares indicate male; circles, female; X, individuals examined in this study; slash, deceased; arrow, proband; M, mutant allele; and plus sign, normal allele. METHODS Figure 2. Results of nucleotide sequencing analysis of exon 1 in patient III:4 of family 1 showing the heterozygous 208delG mutation. The arrow indicates Genomic DNA samples isolated from 148 patients from unre- the position of the mutation. lated families with ADRP and from 54 patients from unrelated families with cone-rod dystrophy or MD were screened to search for mutations in the FSCN2 gene. One hundred control chro- quence. There was a deletion of nucleotide G at the mosomes from 50 normal subjects were further screened for complementary DNA position 208, and this was desig- mutations of this gene. Informed consent was obtained from nated as a 208delG mutation in the FSCN2 gene all patients before their entry into this study. (Figure 2). The nonaffected members did not have this The sequences from exon 1 to exon 5 of the FSCN2 gene mutation, and this mutation cosegregated with the phe- were amplified by polymerase chain reaction. Nine sets of oli- notype of MD (Figure 1). We further screened our pa- gonucleotide primer pairs were used to cover the extent of these tients for mutations in the peripherin/RDS, CRX, and sequences.12 Products of the polymerase chain reaction were GUCY2D genes, and no mutation was detected. We also directly sequenced in the forward and reverse directions on an confirmed that the 208delG mutation was not present in ABI sequencer (model 3100; Applied Biosystems, Foster City, 100 normal control chromosomes. Calif). The clinical features of the 4 Japanese families with ADRP associated with the 208delG mutation have already been re- ported.12 We present herein our findings on the 5 patients from REPORT OF CASES 2 Japanese families with ADMD. The heterozygous 208delG mu- tation in the FSCN2 gene was identified in all affected mem- FAMILY 1, PATIENT III:4 bers from the 2 families (Figure 1). Ophthalmic examinations included best-corrected visual The proband, a 62-year-old man, had a gradual progres- acuity, kinetic visual field examination, slitlamp biomicros- sion of visual impairment, photophobia, and constric- copy, fundus examination, fluorescein angiography, and elec- tion of the visual field during his 40s. In 1992, at age 52, troretinography. Ophthalmoscopic findings were recorded by he visited our clinic to have a detailed assessment of his color fundus photography. Kinetic visual field examinations were eyes. His visual acuity was corrected to 0.70 OD with a performed on the Goldmann perimetry with the V-4-e, I-4-e, I-3-e, and I-2-e targets. 2.0 diopter (D) sphere and to 0.06 OS with a 1.0 D sphere. Electroretinograms (ERGs) were recorded under con- Slitlamp biomicroscopic examination showed nor- trolled conditions that conformed to the standards of the In- mal-appearing cornea, anterior chamber, iris, lens, and ternational Society of Clinical Electrophysiology of Vision.15 vitreous in both eyes. Fundus examination showed the Briefly, photopic ERGs were elicited by a single flash or a 30-Hz mottled appearance of retinal pigment epithelium (RPE) flicker stimulus of red light under light-adapted conditions in the posterior pole bilaterally (Figure 3A). Fluores- (cone-isolated responses); a dim blue flash under dark- cein angiography disclosed diffuse hyperfluorescence adapted conditions (30 minutes) was used for the rod-isolated around the macula in the right eye and oval and round ERGs (rod-isolated responses); and a bright white flash (in- hyperfluorescent lesions in the posterior pole of the left tensity of 1.69 candelas/m2 per second) under dark-adapted con- eye (Figure 4A). ditions was used to elicit the mixed cone-rod responses. The means±SDs of the amplitudes of the ERGs of the normal sub- The rod-isolated, photopic, mixed cone-rod, and jects in our laboratory were: rod-isolated b-wave, 230.1±51.2 30-Hz flicker ERGs were within the normal range µV; photopic a-wave, 57.2±17.1 µV; photopic b-wave, (Figure 5). The patient could not identify the numbers 110.3±22.6 µV; mixed a-wave, 376.3±49.4 µV; mixed b- on the Ishihara plates. wave, 560.2±72.9 µV; and 30-Hz flicker, 127.5±24.1 µV. He experienced an accelerated deterioration of cen- tral visual acuity after his first visit in 1992 at age 52. In RESULTS 2001, his visual acuity had decreased to counting fin- gers in both eyes. Fundus examination at this time showed The 5 affected members from the 2 families with ADMD bilateral atrophic MD, a mottled appearance of the RPE, (Figure 1) had an identical abnormal nucleotide se- which appeared to have progressed since his first visit, (REPRINTED) ARCH OPHTHALMOL / VOL 121, NOV 2003 WWW.ARCHOPHTHALMOL.COM 1614 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 A B C D Figure 3. Fundus photographs of symptomatic patients. A, Patient III:4 of family 1 at age 52 years. The mottled appearance of retinal pigment epithelium in the posterior pole can be seen. B, Same patient at age 62. Atrophic macular degeneration has progressed during the 10 years. C, Patient III:1 of family 2 at age 13 years showing atrophic degeneration in the posterior pole without attenuation of the retinal vessels. D, Same patient at age 23.
Load more

Recommended publications
  • Molecular Effects of Isoflavone Supplementation Human Intervention Studies and Quantitative Models for Risk Assessment
    Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis committee Promotors Prof. Dr Pieter van ‘t Veer Professor of Nutritional Epidemiology Wageningen University Prof. Dr Evert G. Schouten Emeritus Professor of Epidemiology and Prevention Wageningen University Co-promotors Dr Anouk Geelen Assistant professor, Division of Human Nutrition Wageningen University Dr Lydia A. Afman Assistant professor, Division of Human Nutrition Wageningen University Other members Prof. Dr Jaap Keijer, Wageningen University Dr Hubert P.J.M. Noteborn, Netherlands Food en Consumer Product Safety Authority Prof. Dr Yvonne T. van der Schouw, UMC Utrecht Dr Wendy L. Hall, King’s College London This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 20 June 2014 at 13.30 p.m. in the Aula. Vera van der Velpen Molecular effects of isoflavone supplementation: Human intervention studies and quantitative models for risk assessment 154 pages PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-952-0 ABSTRact Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology.
    [Show full text]
  • Null Mutation of the Fascin2 Gene by TALEN Leading to Progressive Hearing Loss and Retinal Degeneration in C57BL/6J Mice
    G3: Genes|Genomes|Genetics Early Online, published on August 6, 2018 as doi:10.1534/g3.118.200405 Null mutation of the Fascin2 gene by TALEN leading to progressive hearing loss and retinal degeneration in C57BL/6J mice Xiang Liu1,3,§, Mengmeng Zhao1,2,§, Yi Xie1,2, §, Ping Li1, Oumei Wang1 , Bingxin Zhou1,2, Linlin Yang1,4, Yao Nie1, Lin Cheng1, Xicheng Song1,5, Changzhu Jin1,3,**, Fengchan Han1,2,* 1Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai264003, Shandong, P. R. China 2Department of Biochemistry and Molecular Biology, Binzhou Medical University, 346 Guanhai Road, Yantai264003, Shandong, P. R. China 3Department of Human Anatomy and Histology and Embryology, Binzhou Medical University, 346 Guanhai Road, Yantai264003, Shandong, P. R. China 4Department of Otorhinolaryngology-Head and Neck Surgery, Yuhuangding Hospital, 20 East Yuhuangding Road, Yantai 264000, Shandong, P.R .China § These authors contribute equally *The First Corresponding Author: [email protected] **The Second Corresponding Author: [email protected] Key Laboratory for Genetic Hearing Disorders in Shandong, Department of Biochemistry and Molecular Biology, Binzhou Medical University, 346 Guanhai Road, Yantai264003, Shandong, P. R. China © The Author(s) 2013. Published by the Genetics Society of America. Abstract Fascin2 (FSCN2) is an actin cross-linking protein that is mainly localized in retinas and in the stereocilia of hair cells. Earlier studies showed that a deletion mutation in human FASCIN2 (FSCN2) gene could cause autosomal dominant retinitis pigmentosa. Recent studies have indicated that a missense mutation in mouse Fscn2 gene (R109H) can contribute to the early onset of hearing loss in DBA/2J mice.
    [Show full text]
  • Fascin (55Kd Actin-Bundling Protein, Singed-Like Protein, P55)
    Fascin (55kD actin-bundling protein, Singed-like protein, p55) Catalog number 144510 Supplier United States Biological Fascin is a actin cross-linking protein.The Fascin gene contains 5 exons and spans 7 kb. It is a 54-58 kilodalton monomeric actin filament bundling protein originally isolated from sea urchin egg but also found in Drosophila and vertebrates, including humans. Fascin (from the Latin for bundle) is spaced at 11 nanometre intervals along the filament. The bundles in cross section are seen to be hexagonally packed, and the longitudinal spacing is compatible with a model where fascin cross-links at alternating 4 and 5 actins. It is calcium insensitive and monomeric. Fascin binds beta-catenin, and colocalizes with it at the leading edges and borders of epithelial and endothelial cells. The role of Fascin in regulating cytoskeletal structures for the maintenance of cell adhesion, coordinating motility and invasion through interactions with signalling pathways is an active area of research especially from the cancer biology perspective. Abnormal fascin expression or function has been implicated in breast cancer, colon cancer, esophageal squamous cell carcinoma, gallbladder cancer and prostate cancer. UniProt Number Q16658 Gene ID FSCN1 Applications Suitable for use in Western Blot. Recommended Dilution Optimal dilutions to be determined by the researcher. Storage and Handling Store at -20˚C for one year. After reconstitution, store at 4˚C for one month. Can also be aliquoted and stored frozen at -20˚C for long term. Avoid repeated freezing and thawing. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap.
    [Show full text]
  • Fascin 2 (FSCN2) Goat Polyclonal Antibody – AP31070PU-N | Origene
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for AP31070PU-N Fascin 2 (FSCN2) Goat Polyclonal Antibody Product data: Product Type: Primary Antibodies Applications: ELISA, IHC Recommended Dilution: Peptide ELISA: Detection Limit: 1/64000. Western Blot: Preliminary experiments gave bands at approx 75kDa and 22kDa in Mouse Eye lysates after 0.05µg/ml antibody staining. Please note that currently we cannot find an explanation in the literature for the bands we observe given the calculated size of 57.4kDa according to NP_001070650.1 and 55.1kDa according to NP_036550.1. Both detected bands were successfully blocked by incubation with the immunizing peptide (and BLAST results with the immunizing peptide sequence did not identify any other proteins to explain the additional bands). Immunohistochemistry: This product was successfully used on Sections of Mouse cochlea as descibed in Reference 1. Reactivity: Canine, Human, Mouse, Rat Host: Goat Clonality: Polyclonal Immunogen: Peptide with sequence from the internal region of the protein sequence according to NP_001070650.1; NP_036550.1. Specificity: This antibody is expected to recognize both reported isoforms (NP_001070650.1 and NP_036550.1). Formulation: Tris saline, pH~7.3 containing 0.02% Sodium Azide as preservative and 0.5% BSA as stabilizer State: Aff - Purified State: Liquid purified Ig fraction Concentration: lot specific Purification: Affinity Chromatgraphy Conjugation: Unconjugated Storage: Store the antibody undiluted at 2-8°C for one month or (in aliquots) at -20°C for longer. Avoid repeated freezing and thawing.
    [Show full text]
  • The R109H Variant of Fascin-2, a Developmentally Regulated Actin Crosslinker in Hair-Cell Stereocilia, Underlies Early-Onset Hearing Loss of DBA/2J Mice
    The Journal of Neuroscience, July 21, 2010 • 30(29):9683–9694 • 9683 Cellular/Molecular The R109H Variant of Fascin-2, a Developmentally Regulated Actin Crosslinker in Hair-Cell Stereocilia, Underlies Early-Onset Hearing Loss of DBA/2J Mice Jung-Bum Shin,1,2 Chantal M. Longo-Guess,5 Leona H. Gagnon,5 Katherine W. Saylor,1,2 Rachel A. Dumont,1,2 Kateri J. Spinelli,1,2 James M. Pagana,1,2 Phillip A. Wilmarth,3,4 Larry L. David,3,4 Peter G. Gillespie,1,2 and Kenneth R. Johnson5 1Oregon Hearing Research Center, 2Vollum Institute, 3Proteomics Shared Resource, and 4Department of Biochemistry, Oregon Health & Science University, Portland, Oregon 97239, and 5The Jackson Laboratory, Bar Harbor, Maine 04609 The quantitative trait locus ahl8 is a key contributor to the early-onset, age-related hearing loss of DBA/2J mice. A nonsynonymous nucleotide substitution in the mouse fascin-2 gene (Fscn2) is responsible for this phenotype, confirmed by wild-type BAC transgene rescue of hearing loss in DBA/2J mice. In chickens and mice, FSCN2 protein is abundant in hair-cell stereocilia, the actin-rich structures comprising the mechanically sensitive hair bundle, and is concentrated toward stereocilia tips of the bundle’s longest stereocilia. FSCN2 expression increases when these stereocilia differentially elongate, suggesting that FSCN2 controls filament growth, stiffens exposed stereocilia, or both. Because ahl8 accelerates hearing loss only in the presence of mutant cadherin 23, a component of hair-cell tip links, mechanotransduction and actin crosslinking must be functionally interrelated. Introduction espin, has very short stereocilia, and is profoundly deaf (Zheng et Hair cells of the inner ear detect and transduce mechanical dis- al., 2000).
    [Show full text]
  • Characterizing Epigenetic Regulation in the Developing Chicken Retina Bejan Abbas Rasoul James Madison University
    James Madison University JMU Scholarly Commons Masters Theses The Graduate School Spring 2018 Characterizing epigenetic regulation in the developing chicken retina Bejan Abbas Rasoul James Madison University Follow this and additional works at: https://commons.lib.jmu.edu/master201019 Part of the Computational Biology Commons, Developmental Biology Commons, Genomics Commons, and the Molecular Genetics Commons Recommended Citation Rasoul, Bejan Abbas, "Characterizing epigenetic regulation in the developing chicken retina" (2018). Masters Theses. 569. https://commons.lib.jmu.edu/master201019/569 This Thesis is brought to you for free and open access by the The Graduate School at JMU Scholarly Commons. It has been accepted for inclusion in Masters Theses by an authorized administrator of JMU Scholarly Commons. For more information, please contact [email protected]. Characterizing Epigenetic Regulation in the Developing Chicken Retina Bejan Abbas Rasoul A thesis submitted to the Graduate Faculty of JAMES MADISON UNIVERSITY In Partial Fulfillment of the Requirements for the degree of Master of Science Department of Biology May 2018 FACULTY COMMITTEE: Committee Chair: Dr. Raymond A. Enke Committee Members/ Readers: Dr. Steven G. Cresawn Dr. Kimberly H. Slekar DEDICATION For my father, who has always put the education of everyone above all else. ii ACKNOWLEDGMENTS I thank my advisor, Dr. Ray Enke, first, for accepting me as his graduate student and second, for provided significant support, advice and time to aid in the competition of my project and thesis. I would also like to thank my committee members not just for their role in this process but for being members of the JMU Biology Department ready to give any help they can.
    [Show full text]
  • Using an Atlas of Gene Regulation Across 44 Human Tissues to Inform Complex Disease- and Trait-Associated Variation
    ARTICLES https://doi.org/10.1038/s41588-018-0154-4 Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation Eric R. Gamazon 1,2,21*, Ayellet V. Segrè 3,4,21*, Martijn van de Bunt 5,6,21, Xiaoquan Wen7, Hualin S. Xi8, Farhad Hormozdiari 9,10, Halit Ongen 11,12,13, Anuar Konkashbaev1, Eske M. Derks 14, François Aguet 3, Jie Quan8, GTEx Consortium15, Dan L. Nicolae16,17,18, Eleazar Eskin9, Manolis Kellis3,19, Gad Getz 3,20, Mark I. McCarthy 5,6, Emmanouil T. Dermitzakis 11,12,13, Nancy J. Cox1 and Kristin G. Ardlie3 We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to meta- bolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40–80%). For most traits, tissue-shared eQTLs underlie a greater proportion of trait associations, although tissue-specific eQTLs have a greater contribution to some traits, such as blood pressure. By integrating information from biological pathways with eQTL target genes and applying a gene-based approach, we validate previously implicated causal genes and pathways, and propose new variant and gene associations for several complex traits, which we replicate in the UK BioBank and BioVU.
    [Show full text]
  • Targeted RP9 Ablation and Mutagenesis in Mouse Photoreceptor Cells by CRISPR-Cas9
    www.nature.com/scientificreports OPEN Targeted RP9 ablation and mutagenesis in mouse photoreceptor cells by CRISPR-Cas9 Received: 24 November 2016 Ji-Neng Lv1,2,*, Gao-Hui Zhou1,2,*, Xuejiao Chen1,2,*, Hui Chen1,2, Kun-Chao Wu1,2, Lue Xiang1,2, Accepted: 17 January 2017 Xin-Lan Lei1,2, Xiao Zhang1,2, Rong-Han Wu1,2 & Zi-Bing Jin1,2 Published: 20 February 2017 Precursor messenger RNA (Pre-mRNA) splicing is an essential biological process in eukaryotic cells. Genetic mutations in many spliceosome genes confer human eye diseases. Mutations in the pre- mRNA splicing factor, RP9 (also known as PAP1), predispose autosomal dominant retinitis pigmentosa (adRP) with an early onset and severe vision loss. However, underlying molecular mechanisms of the RP9 mutation causing photoreceptor degeneration remains fully unknown. Here, we utilize the CRISPR/Cas9 system to generate both the Rp9 gene knockout (KO) and point mutation knock in (KI) (Rp9, c.A386T, P.H129L) which is analogous to the reported one in the retinitis pigmentosa patients (RP9, c.A410T, P.H137L) in 661 W retinal photoreceptor cells in vitro. We found that proliferation and migration were significantly decreased in the mutated cells. Gene expression profiling by RNA- Seq demonstrated that RP associated genes, Fscn2 and Bbs2, were down-regulated in the mutated cells. Furthermore, pre-mRNA splicing of the Fscn2 gene was markedly affected. Our findings reveal a functional relationship between the ubiquitously expressing RP9 and the disease-specific gene, thereafter provide a new insight of disease mechanism in RP9-related retinitis pigmentosa. Retinitis pigmentosa (RP [MIM 268000]) is a group of retinal degenerative disorders with high heritability and heterogeneity, affecting approximately 1 in 4,000 in dividuals1,2 and it is becoming the leading cause of irre- versible midway blindness worldwide.
    [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]
  • Allelic Copy Number Variation in FSCN2 Detected Using Allele-Specific Genotyping and Multiplex Real-Time Pcrs
    Allelic Copy Number Variation in FSCN2 Detected Using Allele-Specific Genotyping and Multiplex Real-Time PCRs Zi-Bing Jin,1 Michiko Mandai,1 Kohei Homma,1 Chie Ishigami,1 Yasuhiko Hirami,1 Nobuhisa Nao-i,2 and Masayo Takahashi1 PURPOSE. Allelic copy number variation (CNV) may alter the or autosomal dominant macular degeneration (ADMD) by sin- functional effects of a heterozygous mutation. The underlying gle-strand conformation polymorphism (SSCP). Mutational mechanisms and their roles in hereditary diseases, however, screening of the FSCN2 gene in Italian, Spanish, or North are largely unknown. In the present study an FSCN2 mutation American families with RP did not identify this mutation with was examined that has been reported, not only in patients with methods based on direct PCR sequencing.4–6 Sixteen nucleo- retinitis pigmentosa (RP), but also in the normal population. tide substitutions including a nonsense mutation were identi- METHODS. Experiments were performed to investigate the gene fied in the Spanish families with RP or macular degeneration, and allele copy numbers of FSCN2 in patients with RP who but the mutations did not cosegregate with the disease, sug- have the c.72delG mutation as well as healthy subjects with or gesting that mutation of FSCN2 is not sufficient to cause RP. 7 without the mutation. A real-time PCR-based genotyping ap- More recently, Zhang et al. screened patients with or without proach was established that used a real-time PCR assay to retinal degeneration for the c.72delG mutation, resulting in the qualify the copy numbers of both the wild-type and mutant identification of 8 of the 242 patients; again, the mutation did alleles of the FSCN2 gene.
    [Show full text]
  • Using an Atlas of Gene Regulation Across 44 Human Tissues to Inform Complex Disease- and Trait-Associated Variation
    Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Gamazon, Eric R. "Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation." Nature Genetics 50, 7 (July 2018): 956–967 © 2018 The Author(s) As Published http://dx.doi.org/10.1038/S41588-018-0154-4 Publisher Springer Nature Version Author's final manuscript Citable link https://hdl.handle.net/1721.1/121227 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ Europe PMC Funders Group Author Manuscript Nat Genet. Author manuscript; available in PMC 2018 December 28. Published in final edited form as: Nat Genet. 2018 July ; 50(7): 956–967. doi:10.1038/s41588-018-0154-4. Europe PMC Funders Author Manuscripts Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation Eric R. Gamazon1,2,§,*, Ayellet V. Segrè3,4,§,*, Martijn van de Bunt5,6,§, Xiaoquan Wen7, Hualin S. Xi8, Farhad Hormozdiari9,10, Halit Ongen11,12,13, Anuar Konkashbaev1, Eske M. Derks14, François Aguet3, Jie Quan8, GTEx Consortium15, Dan L. Nicolae16,17,18, Eleazar Eskin9, Manolis Kellis3,19, Gad Getz3,20, Mark I. McCarthy5,6, Emmanouil T. Dermitzakis11,12,13, Nancy J. Cox1, and Kristin G. Ardlie3 1Division of Genetic Medicine, Department of Medicine,
    [Show full text]
  • Genetic Analysis of Rare Eye Disorders in Pakistani Families
    GENETIC ANALYSIS OF RARE EYE DISORDERS IN PAKISTANI FAMILIES By MUHAMMAD ARIF NADEEM SAQIB Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan 2015 GENETIC ANALYSIS OF RARE EYE DISORDERS IN PAKISTANI FAMILIES A thesis Submitted in the partial fulfillment of the Requirements for the degree of DOCTOR OF PHILOSOPHY In BIOCHEMISTRY/MOLECULAR BIOLOGY By MUHAMMAD ARIF NADEEM SAQIB Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan 2015 CERTIFICATE A thesis submitted in the partial fulfillment of the requirements for the degree of the Doctor of Philosophy. We accept this dissertation as conforming to the required standard. 1 _________________ 2________________ Dr. Muhammad Ansar External Examiner (Supervisor) 3 ____________________ Dr. Muhammad Ansar (Chairperson) Dated: February 09, 2015 DECLARATION I hereby declare that the work presented in the following thesis is my own efforts and that the thesis is my own composition. No part of the thesis has been previously presented for any other degree. Muhammad Arif Nadeem Saqib Dedicated To Muhammad Romman Khan (Late) My Son, who died during the journey of my PhD ACKNOWLEDGEMENT All praise to Allah Almighty, the most beneficent, the most merciful, Who gave me strength and enabled me to undertake and execute this research task. Countless salutations upon the Holy Prophet Hazrat Muhammad (Sallallaho Allaihe Waalahe Wassalum), the city of knowledge for enlightening with the essence of faith in Allah and guiding the mankind, the true path of life. I would like to extend my appreciation to those people, who helped me in one way or another to finish the thesis.
    [Show full text]