MUSCLE X-INACTIVATION PATTERNS AND DYSTROPHIN EXPRESSION IN DUCHENNE MUSCULAR-DYSTROPHY CARRIERS

Muscle pathology, dystrophin expression and X-inactivation patterns we re 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-manif esting carriers showed an increase in the population of centrally nucl eated fibres (9.0 +/- 12.8%; controls, 1.4 +/- 0.3%), frequent fibers with abnormally interrupted dystrophin staining (38 +/- 5%), and, in s ections from three individuals, small numbers of dystrophin-negative f ibers (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-inactiv ation in muscle DNA was nonbiased (50 : 50-60 : 40) in all cases. In t he manifesting carriers both highly biased (90 : 10) and non-biased pa tterns of X-inactivation were found, but no consistent relationship wa s apparent between the patterns of X-inactivation and the proportions of dystrophin-negative fibers. We conclude from studies of the non-man ifesting carriers that the proportion of residual dystrophin is simila r to the relative activation in muscle of the X-chromosome carrying th e wild-type allele. Extreme bias of X-inactivation can be associated w ith early clinical symptoms and severe pathology. However, as non-mani festing and some manifesting adult carriers had identical patterns of X-inactivation, abnormalities in the distribution of dystrophin, as we ll as overall levels of expression, may be important for the developme nt of myopathic pathology.