EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa.
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SUBMITTER: Abd El-Aziz MM
PROVIDER: S-EPMC2719291 | biostudies-literature | 2008 Nov
REPOSITORIES: biostudies-literature
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EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa.
Abd El-Aziz Mai M MM Barragan Isabel I O'Driscoll Ciara A CA Goodstadt Leo L Prigmore Elena E Borrego Salud S Mena Marcela M Pieras Juan I JI El-Ashry Mohamed F MF Safieh Leen Abu LA Shah Amna A Cheetham Michael E ME Carter Nigel P NP Chakarova Christina C Ponting Chris P CP Bhattacharya Shomi S SS Antinolo Guillermo G
Nature genetics 20081005 11
Using a positional cloning approach supported by comparative genomics, we have identified a previously unreported gene, EYS, at the RP25 locus on chromosome 6q12 commonly mutated in autosomal recessive retinitis pigmentosa. Spanning over 2 Mb, this is the largest eye-specific gene identified so far. EYS is independently disrupted in four other mammalian lineages, including that of rodents, but is well conserved from Drosophila to man and is likely to have a role in the modeling of retinal archit ...[more]
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Project description:Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.
| S-EPMC3045506 | biostudies-literature
Project description:Purpose:Retinitis pigmentosa (RP) belongs to a group of inherited retinal diseases with high genetic heterogeneity. This study aimed at identifying the disease-causing variants in patients with autosomal recessive RP. Methods:Three RP families with autosomal recessive inheritance and 139 sporadic RP patients were included. Complete ophthalmic examinations were conducted in all the study subjects. DNA samples were extracted from patients' peripheral blood for whole exome sequencing (WES) analysis. Direct Sanger sequencing was conducted for validating the identified mutations and cosegregation pattern in the RP families. Results:One novel (c.7492G>C:p.Ala2498Pro and c.8422C>T:p.Ala2808Thr) and one reported (c.8012T>A:p.Leu2671X and 6416G>A:p.Cys2139Tyr) pair of compound heterozygous mutations, as well as one reported compound homozygous mutation (c.6416G>A:p.Cys2139Tyr/c.8012T>A:p.Leu2671X), were identified in the EYS gene from three families with autosomal recessive RP. All the mutations were cosegregated with the RP phenotype in the RP families. For the sporadic RP patients, seven novel and seven reported EYS variants were identified in 19 patients, including two novel frameshift (c.8301dupT:p.Asp2767fs and c.9437_9440del:p.Glu3146fs), three novel missense (c.8297G>C:p.Gly2766Ala, c.9052T>C:p.Trp3018Arg, and c.8907T>G:p.Cys2969Trp), and one nonsense (c.490C>T:p.Arg164X) variants. All the novel mutations were confirmed by Sanger sequencing. Most of the variants were located at the C-terminus of the EYS protein. Bioinformatics analyses indicated that all detected variants were damaging or possibly damaging. Conclusions:This study identified eight novel EYS variants and expanded the spectrum of EYS mutations in Chinese RP patients.
| S-EPMC6363637 | biostudies-literature
Project description:EYS mutations demonstrate great genotypic and phenotypic varieties, and are one of the major causes for patients with autosomal recessive retinitis pigmentosa (ARRP). Here, we aim to determine the genetic lesions with phenotypic correlations in two Chinese families with ARRP. Medical histories and ophthalmic documentations were obtained from all participants from the two pedigrees. Targeted next-generation sequencing (NGS) on 189 genes was performed to screen for RP causative mutations in the two families. Two biallelic mutations in EYS, p.[R164*];[C2139Y] and p.[W2640*];[F2954S], were identified in the two families, respectively. EYS p.R164* and p.F2954S are novel alleles associated with RP, while p.C2139Y and p.W2640* are known mutations. Crystal structure modeling on the protein eyes shut homolog encoded by the EYS gene revealed abnormal hydrogen bonds generated by p.C2139Y and p.F2954S, which would likely affect the solubility and cause significant structural changes of the two mutated proteins. In conclusion, our study expands the genotypic spectrums for EYS mutations, and may provide novel insights into the relevant pathogenesis for RP. We also demonstrate targeted NGS approach as a valuable tool for genetic diagnosis.
| S-EPMC4354143 | biostudies-literature
Project description:Mutations in the EYS (eyes shut homolog) gene are a common cause of autosomal recessive (ar) retinitis pigmentosa (RP). Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT), and en face autofluoresence imaging, a cohort of 15 patients (ages 12-51 at first visit), some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK.
| S-EPMC5541311 | biostudies-literature
Project description:Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP.
| S-EPMC2917719 | biostudies-literature
Project description:Mutations in the gene SCAPER (S-phase CyclinA Associated Protein residing in the Endoplasmic Reticulum) have recently been identified as causing syndromic autosomal recessive retinitis pigmentosa with the extraocular manifestations of intellectual disability and attention-deficit/hyperactivity disorder. We present the case of an 11-year-old boy that presented to our clinic with the complaint of decreased night vision. Clinical presentation, family history, and diagnostic imaging were congruent with the diagnosis of autosomal recessive retinitis pigmentosa. Genetic testing of the patient and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Unique to our patient's presentation is the absence of intellectual disability and attention-deficit/hyperactivity disorder, suggesting that SCAPER-associated retinitis pigmentosa can also present without systemic manifestations.
| S-EPMC6349500 | biostudies-literature
Project description:Retinitis pigmentosa (RP) is characterized by degeneration of the retinal photoreceptors and is the leading cause of inherited blindness worldwide. Although few genes are known to cause autosomal recessive RP (arRP), a large proportion of disease-causing genes remain to be revealed. Here we report the identification of SLC7A14, a potential cationic transporter, as a novel gene linked to arRP. Using exome sequencing and direct screening of 248 unrelated patients with arRP, we find that mutations in the SLC7A14 gene account for 2% of cases of arRP. We further demonstrate that SLC7A14 is specifically expressed in the photoreceptor layer of the mammalian retina and its expression increases during postnatal retinal development. In zebrafish, downregulation of slc7a14 expression leads to an abnormal eye phenotype and defective light-induced locomotor response. Furthermore, targeted knockout of Slc7a14 in mice results in retinal degeneration with abnormal ERG response. This suggests that SLC7A14 has an important role in retinal development and visual function.
| S-EPMC3974215 | biostudies-literature
Project description:BackgroundRetinitis pigmentosa is the most important hereditary retinal degenerative disease, which has a high degree of clinical and genetic heterogeneity. More than half of all cases of retinitis pigmentosa are autosomal recessive (arRP), but the gene(s) causing arRP in most families has yet to be identified. The purpose of this study is to identify the genetic basis of severe arRP in a consanguineous Chinese family.MethodsLinkage and haplotype analyses were used to define the chromosomal location of the pathogenic gene in the Chinese arRP family. Direct DNA sequence analysis of the entire coding region and exon-intron boundaries of EYS was used to determine the disease-causing mutation, and to demonstrate that the mutation co-segregates with the disease in the family.ResultsA single nucleotide substitution of G to T at nucleotide 5506 of EYS was identified in the Chinese arRP family. This change caused a substitution of a glutamic acid residue at codon 1,836 by a stop codon TAA (p.E1836X), and resulted in a premature truncated EYS protein with 1,835 amino acids. Three affected siblings in the family were homozygous for the p.E1836X mutation, while the other unaffected family members carried one mutant allele and one normal EYS allele. The nonsense mutation p.E1836X was not detected in 200 unrelated normal controls.ConclusionsThe EYS gene is a recently identified disease-causing gene for retinitis pigmentosa, and encodes the orthologue of Drosophila spacemaker. To date, there are only eight mutations in EYS that have been identified to cause arRP. Here we report one novel homozygous nonsense mutation of EYS in a consanguineous Chinese arRP family. Our study represents the first independent confirmation that mutations in EYS cause arRP. Additionally, this is the first EYS mutation identified in the Chinese population.
| S-EPMC2927534 | biostudies-literature
Project description:With a worldwide prevalence of 1 in 4,000, retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration. More than 30 genes and loci have been implicated in nonsyndromic autosomal-recessive (ar) RP. Genome-wide homozygosity mapping was conducted in one Dutch and one Israeli family affected by arRP. The families were found to share a 5.9 Mb homozygous region on chromosome 2p23.1-p23.3. A missense variant in one of the genes residing in this interval, C2ORF71, has recently been reported to be associated with RP. C2ORF71, encoding a putative protein of 1,288 amino acids, was found to be specifically expressed in human retina. Furthermore, RT-PCR analysis revealed that in the mouse eye, C2orf71 is expressed as early as embryonic day 14. Mutation analysis detected a 1 bp deletion (c.946 del; p.Asn237MetfsX5) segregating with RP in the Dutch family, whereas a nonsense mutation (c.556C > T; p.Gln186X) was identified in the Israeli family. Microsatellite-marker analysis in additional Israeli families revealed cosegregation of a C2ORF71-linked haplotype in one other family, in which a 13 bp deletion (c.2756_2768 del; p.Lys919ThrfsX) was identified. Clinically, patients with mutations in C2ORF71 show signs of typical RP; these signs include poor night vision and peripheral field loss, typical retinal bone-spicule-type pigment deposits, pale appearance of the optic disk, and markedly reduced or completely extinguished electroretinograms. In conclusion, truncating mutations in C2ORF71 were identified in three unrelated families, thereby confirming the involvement of this gene in the etiology of arRP.
| S-EPMC2869006 | biostudies-literature
Project description:Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.
| S-EPMC5142109 | biostudies-literature