DOCSLIB.ORG

A Novel Gene for Autosomal Dominant Stargardt-Like Macular Dystrophy with Homology to the SUR4 Protein Family

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Novel Gene for Autosomal Dominant Stargardt-Like Macular Dystrophy with Homology to the SUR4 Protein Family A Novel Gene for Autosomal Dominant Stargardt-like Macular Dystrophy with Homology to the SUR4 Protein Family Albert O. Edwards,1 Larry A. Donoso,2 and Robert Ritter, III1 PURPOSE. To describe a novel gene causing a Stargardt-like fatty acid biosynthesis in the pathogenesis of macular degen- phenotype in a family with dominant macular dystrophy and eration. The PCR-based assay for the 5-bp deletion will facilitate the exclusion of all known genes within the disease locus. more accurate genetic counseling and identification of other METHODS. Meiotic breakpoint mapping in a family of 2314 branches of the family. (Invest Ophthalmol Vis Sci. 2001;42: individuals enabled refinement of the location of the disease 2652–2663) gene. The genomic organization and expression profile of known and putative genes within the critical region were determined using bioinformatics, cDNA cloning, and RT-PCR. acular dystrophies with subretinal flecks may arise from The coding sequence of genes expressed within the retina was Mmutations at multiple disease loci,1,2 the most common scanned for mutations, by using DNA sequencing. of which is the ABCA4 gene on chromosome 1 that gives rise 3,4 RESULTS. The disease-causing gene (STGD3) was further local- to Stargardt disease (STGD1) or fundus flavimaculatus. We 2,5 ized to 562 kb on chromosome 6 between D6S460 and a new previously reported a founder effect for a dominant condi- polymorphic marker centromeric to D6S1707. Of the four tion (STGD3) phenotypically similar to Stargardt disease local- genes identified within this region, all were expressed in the ized to chromosome 6q.2,6 A genealogical and molecular inves- retina or retinal pigment epithelium. The only coding DNA tigation of several families with autosomal dominant Stargardt- sequence variant identified in these four genes was a 5-bp like macular dystrophy led to the recognition that all studied deletion in exon 6 of ELOVL4. The deletion is predicted to lead families were related through a common founder that immi- to a truncated protein with a net loss of 44 amino acids, grated to North America in 1730.2,5–8 We also showed that the including a dilysine endoplasmic reticulum retention motif. Stargardt-like disease (STGD2), previously reported to be The ELOVL4 gene is the fourth known example of a predicted linked to chromosome 13,9 was actually a branch of the family human protein with homology to mammalian and yeast en- we had been studying on chromosome 6.5 zymes involved in the membrane-bound fatty acid chain elon- Disease-causing mutations segregating within single families gation system. The genomic organization of ELOVL4 and can be difficult to identify with certainty, because all affected primer sets for exon amplification are presented. patients share the identical genomic DNA segment on which CONCLUSIONS. ELOVL4 causes macular dystrophy in this large the founding mutation arose. Thus, all DNA sequence variation family distributed throughout North America and implicates within the disease locus or critical region is shared by all affected patients and segregates with the trait. In addition to the customary criteria for distinguishing between polymor- From the 1Department of Ophthalmology, University of Texas phisms and mutations, exclusion of other potential disease- Southwestern Medical Center, Dallas; and the 2Henry and Corinne causing sequence variation within the disease locus can con- 10 Bower Laboratory, Wills Eye Hospital, Philadelphia, Pennsylvania. firm the mutation. Therefore, it is critical to exclude Supported in part by Grant EY12699 from the National Institutes sequence variation in all genes within the disease locus. of Health (AOE, LAD), Career Development Awards from Research to The disease locus on chromosome 6q14 for this autosomal Prevent Blindness and the Foundation Fighting Blindness (AOE), and dominant Stargardt-like macular dystrophy family has been unrestricted departmental funds from Research to Prevent Blindness (University of Texas Southwestern and Wills Eye Hospital). The Scholl- progressively refined to between novel markers within the maier Foundation, Fort Worth, Texas; the Anne Marie and Thomas B. region defined by D6S1625 and D6S1707 by us and between 11,12 Walker, Jr. Fund for Age-Related Macular Degeneration, Dallas, Texas; D6S460 and D6S391 by other groups. While this manu- and the Walter Center for Macular Degeneration, Dallas, Texas pro- script was in preparation, a 5-bp deletion in the ELOVL4 gene vided additional support at University of Texas Southwestern. The in three branches of this family was reported by Zhang et al.11 Henry and Corinne Bower Laboratory for Macular Degeneration; the In addition to ELOVL4, they reported exclusion of two other Elizabeth C. King Trust; the estates of Margaret Mercer, Harry B. genes within their 3100-kb critical region between D6S460 and Wright, and Martha W. S. Rogers; the Association for Macular Diseases; 11 and Macular Degeneration International, all of Philadelphia, Pennsyl- D6S391. We are aware of eight additional genes within their vania, provided additional support at Wills Eye Hospital. LAD is the reported critical region that were not excluded and thus could Thomas D. Duane Professor of Ophthalmology, Wills Eye Hospital and harbor a disease-causing sequence variation. Herein, we report Jefferson Medical College, Thomas Jefferson University, Philadelphia, our independent identification and characterization of the Pennsylvania. gene for autosomal dominant Stargardt-like dominant macular Submitted for publication March 26, 2001; revised May 25, 2001; accepted June 5, 2001. dystrophy and the exclusion by DNA sequencing of the com- Commercial relationships policy: N. plete coding region of all candidate genes within our 562-kb The publication costs of this article were defrayed in part by page critical region, defined by D6S460 and a novel marker charge payment. This article must therefore be marked “advertise- (260P22.A) centromeric to D6S1707. The expression profile in ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. human retina, genomic organization, and known functional Corresponding author: Albert O. Edwards, Department of Oph- information are presented for 15 genes in or near the critical thalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9057. region for STGD3 that are candidates for other chromosome 6q [email protected] retinopathies. Investigative Ophthalmology & Visual Science, October 2001, Vol. 42, No. 11 2652 Copyright © Association for Research in Vision and Ophthalmology Downloaded from iovs.arvojournals.org on 09/24/2021 IOVS, October 2001, Vol. 42, No. 11 Gene for Dominant Stargardt-like Dystrophy 2653 FIGURE 1. Color photograph of the retina of a 52-year-old family member with autosomal dominant Stargardt-like macular dystrophy, showing RPE atrophy, subretinal flecks, and temporal pallor of the optic nerve. MATERIALS AND METHODS 74°C for 5 minutes. Amplified products were denatured for 4 minutes at 94°C in the presence of formamide stop dye (6.5 ␮l), snap cooled on DNA Extraction ice, resolved at room temperature on 8% denaturing polyacrylamide White blood cells were isolated by centrifugation of whole blood at gels at 80 W, and transferred to nylon membranes (Roche Molecular 1000g and DNA purified with a kit (Masterpure Genomic DNA; Epi- Biochemicals, Indianapolis, IN) overnight. DNA was cross-linked to the centre Technologies, Madison, WI), according to the manufacturer’s membranes for 5 minutes (Photoprep I; Photodyne, Newberlin, WI). instructions. This research was approved by the institutional review The immobilized products were denatured for 10 minutes in 0.4 M boards and followed the tenets of the Declaration of Helsinki. NaOH and neutralized in 2ϫ SSC. An oligonucleotide containing an AC15 repetitive sequence was Polymorphic Marker Identification, 3Ј-tailed with digoxigenin (DIG)-11-dUTP and terminal transferase ac- Amplification, and Analysis cording to the manufacturer’s instructions (Roche Molecular Biochemi- cals) and hybridized to the resolved PCR products at 42°C in 5ϫ SSC, Previously reported primers for short tandem repeat (STR) amplifica- 1% blocking reagent, 0.1% N-laurosarkosine, 0.02% SDS. Hybridized tion were purchased from Research Genetics (Huntsville, AL). Novel membranes were washed in 6ϫ SSC and 0.1% SDS three times for 5 dinucleotide (AC)n repeat motifs were identified using a BLAST 2 Sequences search (available publicly from the National Center for minutes, followed by a single wash in 0.1 M maleic acid, 0.15 NaCl, and Biotechnology Information [NCBI] at http://www.ncbi.nlm.nih.gov/ 0.3% Tween-20 at pH 7.5 for 1 minute. The products were visualized BLAST/) of finished and unfinished genomic sequence within the by incubating membranes with alkaline phosphatase-conjugated anti- STDG3 critical region produced by the Human Chromosome 6 Se- DIG antibody for 60 minutes, washing twice in 0.1 M maleic acid and quencing Group at the Sanger Centre (Cambridgeshire, UK) with an 0.15 M NaCl at pH 7.5 for 15 minutes, followed by a single equilibra- tion in 100 mM Tris-HCl, 100 mM NaCl, and 50 mM MgCL at pH 9.5 (AC)60 sequence motif. Primers were designed in flanking sequence for 2 amplification. Polymerase chain reactions (PCRs) were performed on for 2 minutes. The membranes were incubated with the chromogenic genomic DNA (12.5 ng) in the presence of 1.5 mM MgCl, 1.25 nM each substrate (nitroblue tetrazolium chloride-5-bromo-4-chloro-3-indoyl dNTP, 2.5 pM each primer, and 0.11 U Taq polymerase in a final phosphate 4-toludine sale [NBT/BCIP]) until the desired band intensity volume of 6.5 ␮l under the following conditions: initial denaturation at was achieved. All results were analyzed by at least two independent 95°C for 4 minutes, followed by 30 cycles at 94°C for 10 seconds, 55°C investigators and compared with a control sample (CEPH 1331-01) for for 10 seconds, and 74°C for 10 seconds, and then a final extension at registering genotypes between assays.
Load more

Recommended publications
  • A Multistep Bioinformatic Approach Detects Putative Regulatory
    BMC Bioinformatics BioMed Central Research article Open Access A multistep bioinformatic approach detects putative regulatory elements in gene promoters Stefania Bortoluzzi1, Alessandro Coppe1, Andrea Bisognin1, Cinzia Pizzi2 and Gian Antonio Danieli*1 Address: 1Department of Biology, University of Padova – Via Bassi 58/B, 35131, Padova, Italy and 2Department of Information Engineering, University of Padova – Via Gradenigo 6/B, 35131, Padova, Italy Email: Stefania Bortoluzzi - [email protected]; Alessandro Coppe - [email protected]; Andrea Bisognin - [email protected]; Cinzia Pizzi - [email protected]; Gian Antonio Danieli* - [email protected] * Corresponding author Published: 18 May 2005 Received: 12 November 2004 Accepted: 18 May 2005 BMC Bioinformatics 2005, 6:121 doi:10.1186/1471-2105-6-121 This article is available from: http://www.biomedcentral.com/1471-2105/6/121 © 2005 Bortoluzzi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Searching for approximate patterns in large promoter sequences frequently produces an exceedingly high numbers of results. Our aim was to exploit biological knowledge for definition of a sheltered search space and of appropriate search parameters, in order to develop a method for identification of a tractable number of sequence motifs. Results: Novel software (COOP) was developed for extraction of sequence motifs, based on clustering of exact or approximate patterns according to the frequency of their overlapping occurrences.
    [Show full text]
  • ELOVL4 Gene ELOVL Fatty Acid Elongase 4
    ELOVL4 gene ELOVL fatty acid elongase 4 Normal Function The ELOVL4 gene provides instructions for making a protein that is found primarily in the retina, the specialized light-sensitive tissue that lines the back of the eye. Within the retina, the ELOVL4 protein is produced in specialized light receptor cells ( photoreceptors). The ELOVL4 protein is also found in the brain and skin, but less is known about its activity (expression) in these structures. Inside photoreceptor cells, this protein is located in a cell structure called the endoplasmic reticulum that is involved in protein production, processing, and transport. The ELOVL4 protein plays a role in making a group of fats called very long-chain fatty acids. The protein helps add carbon molecules to long-chain fatty acids, making them very long-chain fatty acids. The function of the very long-chain fatty acids produced by the ELOVL4 protein is unknown. Health Conditions Related to Genetic Changes Stargardt macular degeneration At least three mutations in the ELOVL4 gene have been found to cause Stargardt macular degeneration. These mutations create a premature stop signal in the instructions used to make the ELOVL4 protein. As a result, the protein cannot be retained in the endoplasmic reticulum of photoreceptor cells. Instead, the ELOVL4 protein forms clumps (aggregates). These aggregates cannot make very long-chain fatty acids and may interfere with cell functions, ultimately leading to cell death. The loss of photoreceptor cells causes progressive vision loss in people with Stargardt
    [Show full text]
  • Evolutionarily Conserved ELOVL4 Gene Expression in the Vertebrate Retina
    Evolutionarily Conserved ELOVL4 Gene Expression in the Vertebrate Retina Pamela S. Lagali,1 Jiafan Liu,2 Rajesh Ambasudhan,2 Laura E. Kakuk,2 Steven L. Bernstein,3 Gail M. Seigel,4 Paul W. Wong,1,5 and Radha Ayyagari2,5 PURPOSE. The gene elongation of very long chain fatty acids-4 plays a critical role in retinal cell biology. (Invest Ophthalmol (ELOVL4) has been shown to underlie phenotypically hetero- Vis Sci. 2003;44:2841–2850) DOI:10.1167/iovs.02-0991 geneous forms of autosomal dominant macular degeneration. In this study, the extent of evolutionary conservation and the targardt macular dystrophies are inherited disorders of the existence and localization of retinal expression of this gene Sretina that are characterized by impaired central vision, was investigated across a wide variety of species. cellular atrophy of retinal and retinal pigment epithelial (RPE) METHODS. Southern blot analysis of genomic DNA and bioinfor- cells initiating in the macular region, and the presence of matic analysis using the human ELOVL4 cDNA and protein yellow fundus flecks surrounding the atrophic area resulting sequences, respectively, were performed to identify species in from the subretinal accumulation of lipofuscin-like material.1–4 which ELOVL4 orthologues and/or homologues are present. Both autosomal recessive and autosomal dominant forms of Retinal RNA and protein extracts derived from different spe- Stargardt’s disease (STGD) have been described.5,6 cies were assessed by Northern hybridization and immunoblot Classical or recessive Stargardt’s disease (STGD1; OMIM techniques to assess evolutionary conservation of gene expres- 248200; http://www.ncbi.nlm.nih.gov/omim, provided by the sion.
    [Show full text]
  • Stargardt Phenotype Associated with Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis?
    Genetics Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis? Luigi Donato,1–3 Concetta Scimone,2,3 Carmela Rinaldi,3 Pasquale Aragona,3 Silvana Briuglia,3 Angela D’Ascola,3 Rosalia D’Angelo,3 and Antonina Sidoti2,3 1Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy 2Department of Cutting-Edge Medicine and Therapies, Biomolecular Strategies and Neuroscience, Section of Neuroscience-Applied Molecular Genetics and Predictive Medicine, Istituto Euro Mediterraneo di Scienza e Tecnologia (I.E.ME.S.T.), Palermo, Italy 3Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy Correspondence: Rosalia D’Angelo, PURPOSE. Stargardt disease (STGD) is the most common form of inherited juvenile macular Department of Biomedical and Den- degeneration. It is inherited as autosomal recessive trait (STGD1), although STGD3 and STGD4 tal Sciences and Morphofunctional are inherited as autosomal dominant inheritance pattern. STGD3 is caused by mutations in the Imaging, Division of Molecular Ge- elongation of very long-chain fatty acids-like 4 (ELOVL4) gene encoding for a very long-chain netics and Preventive Medicine, fatty acid elongase. Mutations lead to a truncated Elovl4, lacking of a dilysine motif necessary for University of Messina, via C. Valeria 1, I-98125 Messina, Italy; retention of transmembrane proteins in the endoplasmic reticulum. STGD occurs due to altered [email protected]. synthesis of very long-chain polyunsaturated fatty acids (VLC-PUFA). Our work investigates the role of two variants in the ELOVL4 gene promoter region, c.-236 C>T (rs240307) and c.-90 Submitted: September 11, 2017 G>C (rs62407622), identified in a patient with STGD in transconfiguration.
    [Show full text]
  • Content Based Search in Gene Expression Databases and a Meta-Analysis of Host Responses to Infection
    Content Based Search in Gene Expression Databases and a Meta-analysis of Host Responses to Infection A Thesis Submitted to the Faculty of Drexel University by Francis X. Bell in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2015 c Copyright 2015 Francis X. Bell. All Rights Reserved. ii Acknowledgments I would like to acknowledge and thank my advisor, Dr. Ahmet Sacan. Without his advice, support, and patience I would not have been able to accomplish all that I have. I would also like to thank my committee members and the Biomed Faculty that have guided me. I would like to give a special thanks for the members of the bioinformatics lab, in particular the members of the Sacan lab: Rehman Qureshi, Daisy Heng Yang, April Chunyu Zhao, and Yiqian Zhou. Thank you for creating a pleasant and friendly environment in the lab. I give the members of my family my sincerest gratitude for all that they have done for me. I cannot begin to repay my parents for their sacrifices. I am eternally grateful for everything they have done. The support of my sisters and their encouragement gave me the strength to persevere to the end. iii Table of Contents LIST OF TABLES.......................................................................... vii LIST OF FIGURES ........................................................................ xiv ABSTRACT ................................................................................ xvii 1. A BRIEF INTRODUCTION TO GENE EXPRESSION............................. 1 1.1 Central Dogma of Molecular Biology........................................... 1 1.1.1 Basic Transfers .......................................................... 1 1.1.2 Uncommon Transfers ................................................... 3 1.2 Gene Expression ................................................................. 4 1.2.1 Estimating Gene Expression ............................................ 4 1.2.2 DNA Microarrays ......................................................
    [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]
  • Stargardt Phenotype Associated with Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis?
    Genetics Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis? Luigi Donato,1–3 Concetta Scimone,2,3 Carmela Rinaldi,3 Pasquale Aragona,3 Silvana Briuglia,3 Angela D’Ascola,3 Rosalia D’Angelo,3 and Antonina Sidoti2,3 1Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy 2Department of Cutting-Edge Medicine and Therapies, Biomolecular Strategies and Neuroscience, Section of Neuroscience-Applied Molecular Genetics and Predictive Medicine, Istituto Euro Mediterraneo di Scienza e Tecnologia (I.E.ME.S.T.), Palermo, Italy 3Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy Correspondence: Rosalia D’Angelo, PURPOSE. Stargardt disease (STGD) is the most common form of inherited juvenile macular Department of Biomedical and Den- degeneration. It is inherited as autosomal recessive trait (STGD1), although STGD3 and STGD4 tal Sciences and Morphofunctional are inherited as autosomal dominant inheritance pattern. STGD3 is caused by mutations in the Imaging, Division of Molecular Ge- elongation of very long-chain fatty acids-like 4 (ELOVL4) gene encoding for a very long-chain netics and Preventive Medicine, fatty acid elongase. Mutations lead to a truncated Elovl4, lacking of a dilysine motif necessary for University of Messina, via C. Valeria 1, I-98125 Messina, Italy; retention of transmembrane proteins in the endoplasmic reticulum. STGD occurs due to altered [email protected]. synthesis of very long-chain polyunsaturated fatty acids (VLC-PUFA). Our work investigates the role of two variants in the ELOVL4 gene promoter region, c.-236 C>T (rs240307) and c.-90 Submitted: September 11, 2017 G>C (rs62407622), identified in a patient with STGD in transconfiguration.
    [Show full text]
  • ABSTRACT Using a Bioinformatics Approach to Identify Genes That
    ABSTRACT Using a bioinformatics approach to identify genes that have possible candidacy of association with retinitis pigmentosa: GeneWeaver Natasha Lie Director: Erich J. Baker, Ph.D. Retinitis pigmentosa (RP) is a retinal degenerative disorder that affects about 1 in 3,000 people. The disease is genetic in cause, and currently there is no cure. The genetic cause of the disease may be contributed to one of several different genes, underscoring the complex genetic underpinnings of this disease. The information required to determine which genes are potentially causative for RP may exist, but it is difficult to determine which genes are most suitable for study because of the immense wealth and breadth of available information. In other words, large-scale heterogeneous species-specific data often obfuscates the true causative genetic background of RP. In this study we describe a method of identifying genes that may contribute to RP using the bioinformatics techniques of graph theory and database utilization. We report a potential ranked list of genes in which disruptions are likely causative of RP. APPROVED BY DIRECTOR OF HONORS THESIS: ___________________________________________________ Dr. Erich Baker, School of Engineering and Computer Science APPROVED BY THE HONORS PROGRAM: ______________________________________________ Dr. Elizabeth Corey, Director DATE: _________________________ USING A BIOINFORMATICS APPROACH TO IDENTIFY GENES THAT HAVE POSSIBLE CANDIDACY OF ASSOCIATION WITH RETINITIS PIGMENTOSA: GENEWEAVER A Thesis Submitted to the
    [Show full text]
  • Elovl4 Mrna Distribution in the Developing Mouse Retina and Phy- Logenetic Conservation of Elovl4 Genes
    Molecular Vision 2003; 9:301-7 <http://www.molvis.org/molvis/v9/a42> © 2003 Molecular Vision Received 21 April 2003 | Accepted 13 June 2003 | Published 3 July 2003 Elovl4 mRNA distribution in the developing mouse retina and phy- logenetic conservation of Elovl4 genes Xian-Mei Zhang,1 Zhenglin Yang,2,3 Goutam Karan,2,3 Takao Hashimoto,1 Wolfgang Baehr,2 Xian-Jie Yang,1 Kang Zhang2,3 (The first two authors contributed equally to this publication) 1Department of Ophthalmology and Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA; 2Department of Ophthal- mology and Visual Science and 3Program in Human Molecular Biology and Genetics, University of Utah Health Science Center, Salt Lake City, UT Purpose: Stargardt-like macular dystrophy (STGD3) is an autosomal dominant form of early onset macular degeneration. The disease causing gene ELOVL4 encodes a protein that belongs to a family of proteins functioning in elongation of long chain fatty acids. The purpose of this study is to characterize cross-species conservation of ELOVL4 and investigate its mRNA distribution in the developing mouse eye. Methods: Bovine and porcine orthologs of the human ELOVL4 gene were cloned using RT-PCR method. EST and HTGS databases were searched for orthologs of ELOVL4. Cross-species alignments were performed using ClustalW. In situ hybridizations using murine Elovl4 probes were performed on frozen sections of mouse eyes. Results: Elovl4 orthologs from mammalian to invertebrate species share strong sequence homology with human ELOVL4 at the amino acid level, suggesting functional conservation of Elovl4 during evolution. Expression of Elovl4 in mouse retina begins at E15 during embryogenesis and persists in postnatal stages.
    [Show full text]
  • Genetic Identification and Molecular Modeling Characterization Reveal a Novel PROM1 Mutation in Stargardt4-Like Macular Dystrophy
    www.impactjournals.com/oncotarget/ Oncotarget, 2018, Vol. 9, (No. 1), pp: 122-141 Research Paper: Chromosome Genetic identification and molecular modeling characterization reveal a novel PROM1 mutation in Stargardt4-like macular dystrophy Saber Imani1,2,3,*, Jingliang Cheng2,*, Marzieh Dehghan Shasaltaneh4,5,* Chunli Wei2,6, Lisha Yang2, Shangyi Fu7,8, Hui Zou1,2, Md. Asaduzzaman Khan2, Xianqin Zhang2, Hanchun Chen9, Dianzheng Zhang10, Chengxia Duan11, Hongbin Lv11, Yumei Li8, Rui Chen8 and Junjiang Fu1,2,6 1 Hunan Normal University Medical College, Changsha, Hunan, China 2 Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China 3 Chemical Injuries Research Center, Baqiyatallah Medical Sciences University, Tehran, Iran 4 Laboratory of Neuro-organic Chemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran 5 Laboratory of Systems Biology and Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran 6 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China 7 The Honors College, University of Houston, Houston, TX, USA 8 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA 9 Department of Biochemistry, School of Life Sciences & the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China 10 Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA 11 Department of Ophthalmology, First Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China * These authors have contributed equally to this work Correspondence to: Junjiang Fu, email: [email protected] Keywords: stargardt disease-4 (STGD4); next generation sequencing; PROM1; missense mutation; molecular modeling Received: June 14, 2017 Accepted: August 26, 2017 Published: November 09, 2017 Copyright: Imani et al.
    [Show full text]
  • Diverse Macular Dystrophy Phenotype Caused by a Novel Complex Mutation in the ELOVL4 Gene
    Diverse Macular Dystrophy Phenotype Caused by a Novel Complex Mutation in the ELOVL4 Gene Paul S. Bernstein,1 Jaana Tammur,2,3 Nanda Singh,4 Amy Hutchinson,2 Missy Dixon,4 Chris M. Pappas,4 Norman A. Zabriskie,1 Kang Zhang,5 Konstantin Petrukhin,6 Mark Leppert,4 and Rando Allikmets2,7 PURPOSE. A 5-bp deletion in ELOVL4, a photoreceptor-specific flecks. Stargardt disease (STGD; Mendelian Inheritance in gene, has been associated with autosomal dominant (ad) mac- Man [MIM] 248200) can be inherited as an autosomal reces- ular dystrophy phenotypes in five related families, in which sive (ar) trait (MIM 248200) or an autosomal dominant (ad) phenotypes range from Stargardt-like macular dystrophy trait (MIM 600110; 603786). All recessive forms of STGD (STGD3; Mendelian Inheritance in Man 600110) to pattern have been linked to a locus on 1p32, containing the ABCR dystrophy. This has been the only mutation identified in (ABCA4) gene.1 Mutations in ABCR, a photoreceptor-spe- ELOVL4 to date, which is associated with macular dystrophy cific adenosine triphosphate (ATP)-binding cassette (ABC) phenotypes. In the current study, the potential involvement transporter, are causal in arSTGD2 and in a number of other was investigated of an ELOVL4 gene variation in adSTGD-like retinal diseases, such as recessive cone–rod dystrophy and other macular dystrophy phenotypes segregating in a large (CRD),3 and some forms of autosomal recessive retinitis unrelated pedigree from Utah (K4175). pigmentosa (RP19).4,5 Heterozygous carriers of ABCR vari- ETHODS ant alleles are more susceptible to age-related macular de- M . The entire open reading frame of the ELOVL4 gene 6,7 was analyzed by direct sequencing in a proband from the generation (AMD), a late-onset complex trait.
    [Show full text]
  • Expanding the Clinical Phenotype Associated with ELOVL4 Mutation
    Research Original Investigation Expanding the Clinical Phenotype Associated With ELOVL4 Mutation Study of a Large French-Canadian Family With Autosomal Dominant Spinocerebellar Ataxia and Erythrokeratodermia Maxime Cadieux-Dion, BSc; Maude Turcotte-Gauthier, MSc; Anne Noreau, MSc; Caroline Martin, BSc; Caroline Meloche, MSc; Micheline Gravel, BSc; Christian Allen Drouin, MD; Guy A. Rouleau, MD, PhD, FRCPC; Dang Khoa Nguyen, MD, PhD, FRCPC; Patrick Cossette, MD, PhD, FRCPC Supplemental content at IMPORTANCE The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of jamaneurology.com neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described. OBJECTIVE To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. DESIGN, SETTING, AND PARTICIPANTS A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations. MAIN OUTCOMES AND MEASURES Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. RESULTS We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution.
    [Show full text]