Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

Background: Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the...

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Authors: Juan-Mateu, J, Rodriguez, MJ, Nascimento, A, Jimenez-Mallebrera, C, Gonzalez-Quereda, L, Rivas, E, Paradas, C, Madruga, M, Sanchez-Ayaso, P, Jou, C, Gonzalez-Mera, L, Munell, F, Roig-Quilis, M, Rabasa, M, Hernandez-Lain, A, Diaz-Manera, J, Gallardo, E, Pascual, J, Verdura, E, Colomer, J, Baiget, M, Olive, M, Gallano, P
Format: article
Status:Published version
Publication Date:2012
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p11058
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11058
Access Level:Open access
Keyword:Dystrophin
DMD
Symptomatic carrier
Duchenne muscular dystrophy
Becker muscular dystrophy
X-chromosome inactivation
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spelling Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathyJuan-Mateu, JRodriguez, MJNascimento, AJimenez-Mallebrera, CGonzalez-Quereda, LRivas, EParadas, CMadruga, MSanchez-Ayaso, PJou, CGonzalez-Mera, LMunell, FRoig-Quilis, MRabasa, MHernandez-Lain, ADiaz-Manera, JGallardo, EPascual, JVerdura, EColomer, JBaiget, MOlive, MGallano, PDystrophinDMDSymptomatic carrierDuchenne muscular dystrophyBecker muscular dystrophyX-chromosome inactivationBackground: Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. Methods: We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. Results: Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. Conclusions: Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.BMC2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11058Orphanet Journal of Rare DiseasesISSN: 17501172reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p110582026-06-14T12:41:47Z
dc.title.none.fl_str_mv Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
title Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
spellingShingle Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
Juan-Mateu, J
Dystrophin
DMD
Symptomatic carrier
Duchenne muscular dystrophy
Becker muscular dystrophy
X-chromosome inactivation
title_short Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
title_full Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
title_fullStr Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
title_full_unstemmed Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
title_sort Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy
dc.creator.none.fl_str_mv Juan-Mateu, J
Rodriguez, MJ
Nascimento, A
Jimenez-Mallebrera, C
Gonzalez-Quereda, L
Rivas, E
Paradas, C
Madruga, M
Sanchez-Ayaso, P
Jou, C
Gonzalez-Mera, L
Munell, F
Roig-Quilis, M
Rabasa, M
Hernandez-Lain, A
Diaz-Manera, J
Gallardo, E
Pascual, J
Verdura, E
Colomer, J
Baiget, M
Olive, M
Gallano, P
author Juan-Mateu, J
author_facet Juan-Mateu, J
Rodriguez, MJ
Nascimento, A
Jimenez-Mallebrera, C
Gonzalez-Quereda, L
Rivas, E
Paradas, C
Madruga, M
Sanchez-Ayaso, P
Jou, C
Gonzalez-Mera, L
Munell, F
Roig-Quilis, M
Rabasa, M
Hernandez-Lain, A
Diaz-Manera, J
Gallardo, E
Pascual, J
Verdura, E
Colomer, J
Baiget, M
Olive, M
Gallano, P
author_role author
author2 Rodriguez, MJ
Nascimento, A
Jimenez-Mallebrera, C
Gonzalez-Quereda, L
Rivas, E
Paradas, C
Madruga, M
Sanchez-Ayaso, P
Jou, C
Gonzalez-Mera, L
Munell, F
Roig-Quilis, M
Rabasa, M
Hernandez-Lain, A
Diaz-Manera, J
Gallardo, E
Pascual, J
Verdura, E
Colomer, J
Baiget, M
Olive, M
Gallano, P
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Dystrophin
DMD
Symptomatic carrier
Duchenne muscular dystrophy
Becker muscular dystrophy
X-chromosome inactivation
topic Dystrophin
DMD
Symptomatic carrier
Duchenne muscular dystrophy
Becker muscular dystrophy
X-chromosome inactivation
description Background: Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. Methods: We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. Results: Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. Conclusions: Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.
publishDate 2012
dc.date.none.fl_str_mv 2012
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11058
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11058
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv Orphanet Journal of Rare Diseases
ISSN: 17501172
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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