Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula

[thumbnail of Original Article]
Preview
PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
2MB
[thumbnail of Supplemental Information] MS Word (Supplemental Information)
370kB

Item Type:Article
Title:A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula
Creators Name:Khan, A.O., Becirovic, E., Betz, C., Neuhaus, C., Altmüller, J., Maria Riedmayr, L., Motameny, S., Nürnberg, G., Nürnberg, P. and Bolz, H.J.
Abstract:Deafblindness is mostly due to Usher syndrome caused by recessive mutations in the known genes. Mutation-negative patients therefore either have distinct diseases, mutations in yet unknown Usher genes or in extra-exonic parts of the known genes – to date a largely unexplored possibility. In a consanguineous Saudi family segregating Usher syndrome type 1 (USH1), NGS of genes for Usher syndrome, deafness and retinal dystrophy and subsequent whole-exome sequencing each failed to identify a mutation. Genome-wide linkage analysis revealed two small candidate regions on chromosome 3, one containing the USH3A gene CLRN1, which has never been associated with Usher syndrome in Saudi Arabia. Whole-genome sequencing (WGS) identified a homozygous deep intronic mutation, c.254–649T > G, predicted to generate a novel donor splice site. CLRN1 minigene-based analysis confirmed the splicing of an aberrant exon due to usage of this novel motif, resulting in a frameshift and a premature termination codon. We identified this mutation in an additional two of seven unrelated mutation-negative Saudi USH1 patients. Locus-specific markers indicated that c.254–649T > G(CLRN1) represents a founder allele that may significantly contribute to deafblindness in this population. Our finding underlines the potential of WGS to uncover atypically localized, hidden mutations in patients who lack exonic mutations in the known disease genes.
Keywords:Consanguinity, DNA Mutational Analysis, Exons, Genetic Linkage, Genetic Predisposition To Disease, Genome-Wide Association Study, Genotype, Membrane Proteins, Mutation, Pedigree, Saudi Arabia, Usher Syndromes
Source:Scientific Reports
ISSN:2045-2322
Publisher:Nature Publishing Group
Volume:7
Number:1
Page Range:1411
Date:3 May 2017
Official Publication:https://doi.org/10.1038/s41598-017-01577-8
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library