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Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin.

ABSTRACT: PURPOSE: To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members. METHODS: Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next-generation sequencing. A minigene splicing assay was used to confirm the splicing defects. RESULTS: In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244-2A>C, that disrupted the consensus splice acceptor site of exon 3 was found. The minigene splicing assay revealed that this mutation activated a cryptic splice site within exon 3, causing a 22 bp deletion in the transcript that is predicted to lead to a frameshift followed by premature protein truncation. In family MA13, a novel homozygous null mutation in C8orf37, c.555G>A, p.W185*, was identified. Both mutations segregated with the disease phenotype as expected in a recessive manner and were absent in 8,244 unrelated individuals of South Asian origin. CONCLUSIONS: In this report, we describe C8orf37 mutations that cause retinal dystrophy in two families of Pakistani origin, contributing further data on the phenotype and the spectrum of mutations in this form of retinitis pigmentosa.

SUBMITTER: Ravesh Z

PROVIDER: S-EPMC4357040 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin.

Ravesh Zeinab Z El Asrag Mohammed E ME Weisschuh Nicole N McKibbin Martin M Reuter Peggy P Watson Christopher M CM Baumann Britta B Poulter James A JA Sajid Sundus S Panagiotou Evangelia S ES O'Sullivan James J Abdelhamed Zakia Z Bonin Michael M Soltanifar Mehdi M Black Graeme C M GC Amin-ud Din Muhammad M Toomes Carmel C Ansar Muhammad M Inglehearn Chris F CF Wissinger Bernd B Ali Manir M

Molecular vision 20150307

<h4>Purpose</h4>To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members.<h4>Methods</h4>Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next-generation sequencing. A minigene splicing assay was used to confirm the splicing defects.<h4>Results</h4>In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244-2A ...[more]

PMID: 25802487

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Project description:PurposeThis study was conducted to localize and identify causal mutations associated with autosomal recessive retinitis pigmentosa (RP) in consanguineous familial cases of Pakistani origin.MethodsOphthalmic examinations that included funduscopy and electroretinography (ERG) were performed to confirm the affectation status. Blood samples were collected from all participating individuals, and genomic DNA was extracted. A genome-wide scan was performed, and two-point logarithm of odds (LOD) scores were calculated. Sanger sequencing was performed to identify the causative variants. Subsequently, we performed whole exome sequencing to rule out the possibility of a second causal variant within the linkage interval. Sequence conservation was performed with alignment analyses of PDE6A orthologs, and in silico splicing analysis was completed with Human Splicing Finder version 2.4.1.ResultsA large multigenerational consanguineous family diagnosed with early-onset RP was ascertained. An ophthalmic clinical examination consisting of fundus photography and electroretinography confirmed the diagnosis of RP. A genome-wide scan was performed, and suggestive two-point LOD scores were observed with markers on chromosome 5q. Haplotype analyses identified the region; however, the region did not segregate with the disease phenotype in the family. Subsequently, we performed a second genome-wide scan that excluded the entire genome except the chromosome 5q region harboring PDE6A. Next-generation whole exome sequencing identified a splice acceptor site mutation in intron 16: c.2028-1G>A, which was completely conserved in PDE6A orthologs and was absent in ethnically matched 350 control chromosomes, the 1000 Genomes database, and the NHLBI Exome Sequencing Project. Subsequently, we investigated our entire cohort of RP familial cases and identified a second family who harbored a splice acceptor site mutation in intron 10: c.1408-2A>G. In silico analysis suggested that these mutations will result in the elimination of wild-type splice acceptor sites that would result in either skipping of the respective exon or the creation of a new cryptic splice acceptor site; both possibilities would result in retinal photoreceptor cells that lack PDE6A wild-type protein.Conclusionswe report two splice acceptor site variations in PDE6A in consanguineous Pakistani families who manifested cardinal symptoms of RP. Taken together with our previously published work, our data suggest that mutations in PDE6A account for about 2% of the total genetic load of RP in our cohort and possibly in the Pakistani population as well.

Dataset Information

Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin.

Publications

Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin.

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