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A novel CRX frameshift mutation causing cone-rod dystrophy in a Chinese family: A case report.

ABSTRACT: Cone-rod dystrophy (CORD) is an inherited, progressive retinal disorder with genetic and phenotypic heterogeneity. Here, we aimed to identify the pathogenic mutation in affected individuals in a Chinese family with autosomal dominant cone-rod dystrophy (adCORD).Genomic DNA and clinical examination results were collected from a Chinese family presenting with adCORD. The candidate disease-causing mutations were screened with whole-exome sequencing (WES) and bioinformatics analyses. Sanger sequencing was used for validation and cosegregation analysis.A novel frameshift mutation (NM_000554.4; c.538dupG:p.Val180fs) in exon 4 of the CRX gene was identified in all affected individuals in the Chinese family with adCORD. Cosegregation analysis confirmed that this mutation was cosegregated with the disease. This variant, which results in premature termination of the protein, was absent from all public variant databases or internal exome databases.We used whole-exome sequencing to identify a novel CRX mutation causing adCORD in a Chinese family. This study broadens the known pathogenic mutation spectrum of the CRX gene and shows the potential of WES in identifying the pathogenic mutations of CORD disease.

SUBMITTER: Wang L

PROVIDER: S-EPMC6133598 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A novel CRX frameshift mutation causing cone-rod dystrophy in a Chinese family: A case report.

Wang Lihua L Qi Anhui A Pan Hong H Liu Beihong B Feng Jingjing J Chen Wei W Wang Binbin B

Medicine 20180801 32

<h4>Background</h4>Cone-rod dystrophy (CORD) is an inherited, progressive retinal disorder with genetic and phenotypic heterogeneity. Here, we aimed to identify the pathogenic mutation in affected individuals in a Chinese family with autosomal dominant cone-rod dystrophy (adCORD).<h4>Methods</h4>Genomic DNA and clinical examination results were collected from a Chinese family presenting with adCORD. The candidate disease-causing mutations were screened with whole-exome sequencing (WES) and bioin ...[more]

PMID: 30095615

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Project description:UnlabelledMutations in RPGRIP1 are associated with early onset retinal degenerations in humans and dogs. Dogs homozygous for a 44 bp insertion including a polyA(29) tract potentially leading to premature truncation of the protein, show cone rod degeneration. This is rapid and blinding in a colony of dogs in which the mutation was characterised but in dogs with the same mutation in the pet population there is very variable disease severity and rate of progression.ObjectiveWe hypothesized that this variability must be associated with leakiness of the RPGRIP1 mutation, allowing continued RPGRIP1 production. The study was designed to discover mechanisms that might allow such leakiness.MethodsWe analysed alternate start sites and splicing of RPGRIP1 transcripts; variability of polyA(n) length in the insertion and slippage at polyA(n) during transcription/translation.Results and significanceWe observed a low rate of use of alternative start codons having potential to allow forms of transcript not including the insertion, with the possibility of encoding truncated functional RPGRIP1 protein isoforms. Complex alternative splicing was observed, but did not increase this potential. Variable polyA(n) length was confirmed in DNA from different RPGRIP1(-/-) dogs, yet polyA(n) variability did not correspond with the clinical phenotypes and no individual was found that carried a polyA(n) tract capable of encoding an in-frame variant. Remarkably though, in luciferase reporter gene assays, out-of-frame inserts still allowed downstream reporter gene expression at some 40% of the efficiency of in-frame controls. This indicates a major role of transcriptional or translational frameshifting in RPGRIP1 expression. The known slippage of reverse transcriptases as well as RNA polymerases and thermostable DNA polymerases on oligoA homopolymers meant that we could not distinguish whether the majority of slippage was transcriptional or translational. This leakiness at the mutation site may allow escape from severe effects of the mutation for some dogs.

Project description:To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog.Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy.A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate.Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.

Project description:RationaleGenetic elucidation of cone-dominated retinal dystrophies in Indian subcontinent is much needed to identify and catalog underlying genetic defects. In this context, the present study recruited a consanguineous Indian family affected with autosomal recessive cone dystrophy (CD). Considering the huge genetic heterogeneity and recessive inheritance of the disease, we chose to dissect out causal variant in this family by whole exome sequencing (WES).Patient concernsIn the recruited family, three of the six siblings had complaints of poor visual acuity, photophobia, and disturbed colour vision since early childhood. Fundus examination disclosed vascular attenuation and macular retinal pigment epithelium (RPE) changes in all the affected siblings, signifying degeneration of photoreceptor cells.DiagnosisComplete clinical investigation and electroretinography studies led to the diagnosis of cone dystrophy in three siblings of the family.InterventionsDetailed ophthalmic examination, including family history, visual function testing, and retinal imaging, was performed. We captured and sequenced exomes of 2 affected siblings and their mother using SureSelect Human All Exon V5 Kit on Illumina HiSeq 2000/2500 platform with 100 bp paired-end sequencing method. Candidates after data analysis were screened by segregation analysis and Sanger sequencing. Considering recessive inheritance and consanguinity in the pedigree, we attempted to map large loci homozygous by descent in the genome of patients using exome sequencing variants. Extensive protein modeling was carried out to assess possible consequences of the identified variant on the 3-dimensional structure of the protein.OutcomesWES generated more than 65,000 variants for each individual. Assuming recessive inheritance, 13,026 variants were selected. Further filtering on the basis of their position in gene, class, and minor allele frequency constricted the huge list to 12 rare variants. Finally, we ascertained a single base deletion c.1148delC (p.Thr383fs) in the gene CNGB3 as the causal variant. This is a recurrent frameshift mutation resulting in truncated CNGB3 protein. We mapped a large 15-Mb stretch of homozygous markers spanning the causal variant in the proband. The gene CNGB3 encodes modulatory subunit of cyclic nucleotide-gated channels in cone photoreceptors. Protein modeling reveals loss of 2 transmembrane helices and conserved CAP_ED domain in truncated CNGB3, which eventually is predicted to form nonfunctional channels and hamper phototransduction.LessonsWe have identified a recurrent mutation c.1148delC (p.Thr383fs) in CNGB3 for autosomal recessive CD. The present report provides the first description of CNGB3 mutation from India. It is also the foremost investigation of familial CD in Indian patients; therefore, it presents the primary genetic etiology of CD in India.

Dataset Information

A novel CRX frameshift mutation causing cone-rod dystrophy in a Chinese family: A case report.

Publications

A novel CRX frameshift mutation causing cone-rod dystrophy in a Chinese family: A case report.

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