An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome

Abstract Alternate splicing is a critical regulator of gene expression in eukaryotes, however genetic mutations can cause erroneous splicing and disease. Most recorded splicing disorders are caused by mutations of splice donor/acceptor sites, however intronic mutations can affect splicing. Clinical...

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Autores principales:	Jacqueline M. Ogier, Benedicta D. Arhatari, Marina R. Carpinelli, Bradley K. McColl, Michael A. Wilson, Rachel A. Burt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dccb49ac7e9d41fc8ef1bf8b1792125f
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spelling	oai:doaj.org-article:dccb49ac7e9d41fc8ef1bf8b1792125f2021-12-02T15:08:42ZAn intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome10.1038/s41598-018-23856-82045-2322https://doaj.org/article/dccb49ac7e9d41fc8ef1bf8b1792125f2018-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-23856-8https://doaj.org/toc/2045-2322Abstract Alternate splicing is a critical regulator of gene expression in eukaryotes, however genetic mutations can cause erroneous splicing and disease. Most recorded splicing disorders are caused by mutations of splice donor/acceptor sites, however intronic mutations can affect splicing. Clinical exome analyses largely ignore intronic sequence, limiting the detection of mutations to within coding regions. We describe ‘Trooper’, a novel mouse model of CHARGE syndrome harbouring a pathogenic point mutation in Chd7. The mutation is 18 nucleotides upstream of exon 10 and creates a cryptic acceptor site, causing exon skipping and partial intron retention. This mutation, though detectable in exome sequence, was initially dismissed by computational filtering due to its intronic location. The Trooper strain exhibited many of the previously described CHARGE-like anomalies of CHD7 deficient mouse lines; including hearing impairment, vestibular hypoplasia and growth retardation. However, more common features such as facial asymmetry and circling were rarely observed. Recognition of these characteristic features prompted manual reexamination of Chd7 sequence and subsequent validation of the intronic mutation, highlighting the importance of phenotyping alongside exome analyses. The Trooper mouse serves as a valuable model of atypical CHARGE syndrome and reveals a molecular mechanism that may underpin milder clinical presentation of the syndrome.Jacqueline M. OgierBenedicta D. ArhatariMarina R. CarpinelliBradley K. McCollMichael A. WilsonRachel A. BurtNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jacqueline M. Ogier Benedicta D. Arhatari Marina R. Carpinelli Bradley K. McColl Michael A. Wilson Rachel A. Burt An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome
description	Abstract Alternate splicing is a critical regulator of gene expression in eukaryotes, however genetic mutations can cause erroneous splicing and disease. Most recorded splicing disorders are caused by mutations of splice donor/acceptor sites, however intronic mutations can affect splicing. Clinical exome analyses largely ignore intronic sequence, limiting the detection of mutations to within coding regions. We describe ‘Trooper’, a novel mouse model of CHARGE syndrome harbouring a pathogenic point mutation in Chd7. The mutation is 18 nucleotides upstream of exon 10 and creates a cryptic acceptor site, causing exon skipping and partial intron retention. This mutation, though detectable in exome sequence, was initially dismissed by computational filtering due to its intronic location. The Trooper strain exhibited many of the previously described CHARGE-like anomalies of CHD7 deficient mouse lines; including hearing impairment, vestibular hypoplasia and growth retardation. However, more common features such as facial asymmetry and circling were rarely observed. Recognition of these characteristic features prompted manual reexamination of Chd7 sequence and subsequent validation of the intronic mutation, highlighting the importance of phenotyping alongside exome analyses. The Trooper mouse serves as a valuable model of atypical CHARGE syndrome and reveals a molecular mechanism that may underpin milder clinical presentation of the syndrome.
format	article
author	Jacqueline M. Ogier Benedicta D. Arhatari Marina R. Carpinelli Bradley K. McColl Michael A. Wilson Rachel A. Burt
author_facet	Jacqueline M. Ogier Benedicta D. Arhatari Marina R. Carpinelli Bradley K. McColl Michael A. Wilson Rachel A. Burt
author_sort	Jacqueline M. Ogier
title	An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome
title_short	An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome
title_full	An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome
title_fullStr	An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome
title_full_unstemmed	An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome
title_sort	intronic mutation in chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of charge syndrome
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/dccb49ac7e9d41fc8ef1bf8b1792125f
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An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome

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