title: Muscle X-inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers.
abstract: Muscle pathology, dystrophin expression and X-inactivation patterns were studied in the muscle of five asymptomatic females heterozygous for deletions in the dystrophin gene (non-manifesting carriers) and five symptomatic carriers (manifesting carriers). Muscle from the non-manifesting carriers showed an increase in the population of centrally nucleated fibres (9.0 +/- 2.8%; controls, 1.4 +/- 0.3%), frequent fibers with abnormally interrupted dystrophin staining (38 +/- 5%), and, in sections from three individuals, small numbers of dystrophin-negative fibers (1-4%). The amount of dystrophin measured by immunoblotting was reduced to 64 +/- 5% (P < 0.001 n = 5) of normal. The pattern of X-inactivation in muscle DNA was non-biased (50: 50-60: 40) in all cases. In the manifesting carriers both highly biased (90: 10) and non-biased patterns of X-inactivation were found, but no consistent relationship was apparent between the patterns of X-inactivation and the proportions of dystrophin-negative fibers. We conclude from studies of the non-manifesting carriers that the proportion of residual dystrophin is similar to the relative activation in muscle of the X-chromosome carrying the wild-type allele. Extreme bias of X-inactivation can be associated with early clinical symptoms and severe pathology. However, as non-manifesting and some manifesting adult carriers had identical patterns of X-inactivation, abnormalities in the distribution of dystrophin, as well as overall levels of expression, may be important for the development of myopathic pathology.
authors.affiliation: Genetics Laboratory, University of Oxford, U.K.
authors.forename: P M
authors.initials: PM
authors.lastname: Matthews
authors.forename: D
authors.initials: D
authors.lastname: Benjamin
authors.forename: I
authors.initials: I
authors.lastname: Van Bakel
authors.forename: M V
authors.initials: MV
authors.lastname: Squier
authors.forename: L V
authors.initials: LV
authors.lastname: Nicholson
authors.forename: C
authors.initials: C
authors.lastname: Sewry
authors.forename: P R
authors.initials: PR
authors.lastname: Barnes
authors.forename: J
authors.initials: J
authors.lastname: Hopkin
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.forename: D
authors.initials: D
authors.lastname: Hilton-Jones
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003402:Creatine Kinase / Q000097:blood; D004303:Dosage Compensation, Genetic; D016189:Dystrophin / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009132:Muscles / Q000473:pathology; D009136:Muscular Dystrophies / Q000097:blood / Q000235:genetics* / Q000473:pathology; D014960:X Chromosome
chemical_list: D016189:Dystrophin; D003402:Creatine Kinase