Abstract
BackgroundAlthough 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.MethodsEighteen 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 DMD 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.ResultsThe 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.ConclusionsThis is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total DMD transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype.
Highlights
Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have been reported
Methylation analysis at the androgen receptor locus represents the most used assay: in contrast to direct methods based on expression analysis of polymorphic X-linked genes, AR assay is an indirect method based on differential methylation on active and inactive X chromosome; it is considered an accurate test as high correlation has been demonstrated with results obtained from direct expression analysis
Considering our results along with those reported in the literature, X-inactivation aetiology has been definitively ruled out as an explanation of symptomatic phenotype in female carriers
Summary
Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Duchenne and Becker muscular dystrophies (DMD, MIM#310200 and BMD, MIM#300376) are X-linked recessive conditions caused by mutations in the dystrophin gene. Both DMD and BMD usually affect males, with the majority of female carriers of DMD mutations being asymptomatic, often presenting with high serum creatine kinase (CK) levels as the only clinical sign. A study conducted in the Netherlands, taking into account muscle symptoms and pure cardiac presentation, revealed a higher proportion of carriers manifesting symptoms, i.e. 22% [5]
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