Absence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.

Spinal Muscular Atrophy is caused by homozygous loss of SMN1. All patients retain at least one copy of SMN2 which produces an identical protein but at lower levels due to a silent mutation in exon 7 which results in predominant exclusion of the exon. Therapies targeting the splicing of SMN2 exon 7 h...

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Autores principales:	Thomas Koed Doktor, Lisbeth Dahl Schrøder, Henriette Skovgaard Andersen, Sabrina Brøner, Anna Kitewska, Charlotte Brandt Sørensen, Brage Storstein Andresen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c49b99396dc74de591f148dc0842cbe3
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spelling	oai:doaj.org-article:c49b99396dc74de591f148dc0842cbe32021-11-18T08:17:22ZAbsence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.1932-620310.1371/journal.pone.0098841https://doaj.org/article/c49b99396dc74de591f148dc0842cbe32014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24892836/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Spinal Muscular Atrophy is caused by homozygous loss of SMN1. All patients retain at least one copy of SMN2 which produces an identical protein but at lower levels due to a silent mutation in exon 7 which results in predominant exclusion of the exon. Therapies targeting the splicing of SMN2 exon 7 have been in development for several years, and their efficacy has been measured using either in vitro cellular assays or in vivo small animal models such as mice. In this study we evaluated the potential for constructing a mini-pig animal model by introducing minimal changes in the endogenous porcine Smn1 gene to maintain the native genomic structure and regulation. We found that while a Smn2-like mutation can be introduced in the porcine Smn1 gene and can diminish the function of the ESE, it would not recapitulate the splicing pattern seen in human SMN2 due to absence of a functional ISS immediately downstream of exon 7. We investigated the ISS region and show here that the porcine ISS is inactive due to disruption of a proximal hnRNP A1 binding site, while a distal hnRNP A1 binding site remains functional but is unable to maintain the functionality of the ISS as a whole.Thomas Koed DoktorLisbeth Dahl SchrøderHenriette Skovgaard AndersenSabrina BrønerAnna KitewskaCharlotte Brandt SørensenBrage Storstein AndresenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e98841 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thomas Koed Doktor Lisbeth Dahl Schrøder Henriette Skovgaard Andersen Sabrina Brøner Anna Kitewska Charlotte Brandt Sørensen Brage Storstein Andresen Absence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.
description	Spinal Muscular Atrophy is caused by homozygous loss of SMN1. All patients retain at least one copy of SMN2 which produces an identical protein but at lower levels due to a silent mutation in exon 7 which results in predominant exclusion of the exon. Therapies targeting the splicing of SMN2 exon 7 have been in development for several years, and their efficacy has been measured using either in vitro cellular assays or in vivo small animal models such as mice. In this study we evaluated the potential for constructing a mini-pig animal model by introducing minimal changes in the endogenous porcine Smn1 gene to maintain the native genomic structure and regulation. We found that while a Smn2-like mutation can be introduced in the porcine Smn1 gene and can diminish the function of the ESE, it would not recapitulate the splicing pattern seen in human SMN2 due to absence of a functional ISS immediately downstream of exon 7. We investigated the ISS region and show here that the porcine ISS is inactive due to disruption of a proximal hnRNP A1 binding site, while a distal hnRNP A1 binding site remains functional but is unable to maintain the functionality of the ISS as a whole.
format	article
author	Thomas Koed Doktor Lisbeth Dahl Schrøder Henriette Skovgaard Andersen Sabrina Brøner Anna Kitewska Charlotte Brandt Sørensen Brage Storstein Andresen
author_facet	Thomas Koed Doktor Lisbeth Dahl Schrøder Henriette Skovgaard Andersen Sabrina Brøner Anna Kitewska Charlotte Brandt Sørensen Brage Storstein Andresen
author_sort	Thomas Koed Doktor
title	Absence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.
title_short	Absence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.
title_full	Absence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.
title_fullStr	Absence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.
title_full_unstemmed	Absence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.
title_sort	absence of an intron splicing silencer in porcine smn1 intron 7 confers immunity to the exon skipping mutation in human smn2.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/c49b99396dc74de591f148dc0842cbe3
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Absence of an intron splicing silencer in porcine Smn1 intron 7 confers immunity to the exon skipping mutation in human SMN2.

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