Universität zu Köln

Khan, Arif O., Becirovic, Elvir ORCID: 0000-0001-8801-0649, Betz, Christian, Neuhaus, Christine, Altmueller, Janine, Riedmayr, Lisa Maria, Motameny, Susanne, Nuernberg, Gudrun, Nuernberg, Peter and Bolz, Hanno J. (2017). A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula. Sci Rep, 7. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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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 minigenebased 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Khan, Arif O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Becirovic, Elvir UNSPECIFIED orcid.org/0000-0001-8801-0649 UNSPECIFIED Betz, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuhaus, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Riedmayr, Lisa Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Motameny, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolz, Hanno J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-231379
DOI:	10.1038/s41598-017-01577-8
Journal or Publication Title:	Sci Rep
Volume:	7
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEARING-LOSS; LINKAGE ANALYSIS; GENETIC-VARIATION; SYNDROME TYPE-3; VARIANTS; PROTEIN; DISEASE; DEGENERATION; ASSOCIATION; DIAGNOSIS Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23137