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

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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Arif O. Khan, Elvir Becirovic, Christian Betz, Christine Neuhaus, Janine Altmüller, Lisa Maria Riedmayr, Susanne Motameny, Gudrun Nürnberg, Peter Nürnberg, Hanno J. Bolz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/acd4a01b3c5e4eb5a3ff8a46299b85c7
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:acd4a01b3c5e4eb5a3ff8a46299b85c7
record_format	dspace
spelling	oai:doaj.org-article:acd4a01b3c5e4eb5a3ff8a46299b85c72021-12-02T12:32:02ZA deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula10.1038/s41598-017-01577-82045-2322https://doaj.org/article/acd4a01b3c5e4eb5a3ff8a46299b85c72017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01577-8https://doaj.org/toc/2045-2322Abstract 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.Arif O. KhanElvir BecirovicChristian BetzChristine NeuhausJanine AltmüllerLisa Maria RiedmayrSusanne MotamenyGudrun NürnbergPeter NürnbergHanno J. BolzNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arif O. Khan Elvir Becirovic Christian Betz Christine Neuhaus Janine Altmüller Lisa Maria Riedmayr Susanne Motameny Gudrun Nürnberg Peter Nürnberg Hanno J. Bolz A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula
description	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.
format	article
author	Arif O. Khan Elvir Becirovic Christian Betz Christine Neuhaus Janine Altmüller Lisa Maria Riedmayr Susanne Motameny Gudrun Nürnberg Peter Nürnberg Hanno J. Bolz
author_facet	Arif O. Khan Elvir Becirovic Christian Betz Christine Neuhaus Janine Altmüller Lisa Maria Riedmayr Susanne Motameny Gudrun Nürnberg Peter Nürnberg Hanno J. Bolz
author_sort	Arif O. Khan
title	A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula
title_short	A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula
title_full	A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula
title_fullStr	A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula
title_full_unstemmed	A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula
title_sort	deep intronic clrn1 (ush3a) founder mutation generates an aberrant exon and underlies severe usher syndrome on the arabian peninsula
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/acd4a01b3c5e4eb5a3ff8a46299b85c7
work_keys_str_mv	AT arifokhan adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT elvirbecirovic adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT christianbetz adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT christineneuhaus adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT janinealtmuller adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT lisamariariedmayr adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT susannemotameny adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT gudrunnurnberg adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT peternurnberg adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT hannojbolz adeepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT arifokhan deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT elvirbecirovic deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT christianbetz deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT christineneuhaus deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT janinealtmuller deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT lisamariariedmayr deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT susannemotameny deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT gudrunnurnberg deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT peternurnberg deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula AT hannojbolz deepintronicclrn1ush3afoundermutationgeneratesanaberrantexonandunderliessevereushersyndromeonthearabianpeninsula
_version_	1718394234723106816

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

Ejemplares similares