Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype

<p>Abstract</p> <p>Background</p> <p>Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneou...

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Main Authors: Brioschi Simona, Gualandi Francesca, Scotton Chiara, Armaroli Annarita, Bovolenta Matteo, Falzarano Maria S, Sabatelli Patrizia, Selvatici Rita, D’Amico Adele, Pane Marika, Ricci Giulia, Siciliano Gabriele, Tedeschi Silvana, Pini Antonella, Vercelli Liliana, De Grandis Domenico, Mercuri Eugenio, Bertini Enrico, Merlini Luciano, Mongini Tiziana, Ferlini Alessandra
Format: Article
Language:English
Published: BMC 2012-08-01
Series:BMC Medical Genetics
Subjects:
Online Access:http://www.biomedcentral.com/1471-2350/13/73
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author Brioschi Simona
Gualandi Francesca
Scotton Chiara
Armaroli Annarita
Bovolenta Matteo
Falzarano Maria S
Sabatelli Patrizia
Selvatici Rita
D’Amico Adele
Pane Marika
Ricci Giulia
Siciliano Gabriele
Tedeschi Silvana
Pini Antonella
Vercelli Liliana
De Grandis Domenico
Mercuri Eugenio
Bertini Enrico
Merlini Luciano
Mongini Tiziana
Ferlini Alessandra
author_facet Brioschi Simona
Gualandi Francesca
Scotton Chiara
Armaroli Annarita
Bovolenta Matteo
Falzarano Maria S
Sabatelli Patrizia
Selvatici Rita
D’Amico Adele
Pane Marika
Ricci Giulia
Siciliano Gabriele
Tedeschi Silvana
Pini Antonella
Vercelli Liliana
De Grandis Domenico
Mercuri Eugenio
Bertini Enrico
Merlini Luciano
Mongini Tiziana
Ferlini Alessandra
author_sort Brioschi Simona
collection DOAJ
description <p>Abstract</p> <p>Background</p> <p>Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial.</p> <p>Methods</p> <p>Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative <it>DMD</it> gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females.</p> <p>Results</p> <p>The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers.</p> <p>Conclusions</p> <p>This is the first study deeply exploring the <it>DMD</it> transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of <it>DMD</it> gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total <it>DMD</it> transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype.</p>
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spelling doaj.art-1df9a4b3d5d44be1b37bee3c77f270e42022-12-22T00:01:32ZengBMCBMC Medical Genetics1471-23502012-08-011317310.1186/1471-2350-13-73Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotypeBrioschi SimonaGualandi FrancescaScotton ChiaraArmaroli AnnaritaBovolenta MatteoFalzarano Maria SSabatelli PatriziaSelvatici RitaD’Amico AdelePane MarikaRicci GiuliaSiciliano GabrieleTedeschi SilvanaPini AntonellaVercelli LilianaDe Grandis DomenicoMercuri EugenioBertini EnricoMerlini LucianoMongini TizianaFerlini Alessandra<p>Abstract</p> <p>Background</p> <p>Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial.</p> <p>Methods</p> <p>Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative <it>DMD</it> gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females.</p> <p>Results</p> <p>The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers.</p> <p>Conclusions</p> <p>This is the first study deeply exploring the <it>DMD</it> transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of <it>DMD</it> gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total <it>DMD</it> transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype.</p>http://www.biomedcentral.com/1471-2350/13/73DystrophinopathyFemale carriersX-inactivationTranscriptional balancing
spellingShingle Brioschi Simona
Gualandi Francesca
Scotton Chiara
Armaroli Annarita
Bovolenta Matteo
Falzarano Maria S
Sabatelli Patrizia
Selvatici Rita
D’Amico Adele
Pane Marika
Ricci Giulia
Siciliano Gabriele
Tedeschi Silvana
Pini Antonella
Vercelli Liliana
De Grandis Domenico
Mercuri Eugenio
Bertini Enrico
Merlini Luciano
Mongini Tiziana
Ferlini Alessandra
Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype
BMC Medical Genetics
Dystrophinopathy
Female carriers
X-inactivation
Transcriptional balancing
title Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype
title_full Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype
title_fullStr Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype
title_full_unstemmed Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype
title_short Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype
title_sort genetic characterization in symptomatic female dmd carriers lack of relationship between x inactivation transcriptional dmd allele balancing and phenotype
topic Dystrophinopathy
Female carriers
X-inactivation
Transcriptional balancing
url http://www.biomedcentral.com/1471-2350/13/73
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