MYOTONIC-DYSTROPHY - SIZE-DEPENDENT AND SEX-DEPENDENT DYNAMICS OF CTGMEIOTIC INSTABILITY, AND SOMATIC MOSAICISM

Myotonic dystrophy (DM) is a progressive neuromuscular disorder which results from elongations of an unstable (CTG)n repeat, located in the 3' untranslated region of the DM gene. A correlation has been demonstr ated between the increase in the repeat number of this sequence and th e severity of the disease. However, the clinical status of patients ca nnot be unambigously ascertained solely on the basis of the number of CTG repeats. Moreover, the exclusive maternal inheritance of the conge nital form remains unexplained. Our observation of differently sized r epeats in various DM tissues from the same individual may explain why the size of the mutation observed in lymphocytes does not necessarily correlate with the severity and nature of symptoms. Through a molecula r and genetic study of 142 families including 418 DM patients, we have investigated the dynamics of the CTG repeat meiotic instability. A po sitive correlation between the size of the repeat and the intergenerat ional enlargement was observed similarly through male and female meios es for less-than-or-equal-to 0.5-kb CTG sequences. Beyond 0.5 kb, the intergenerational variation was more important through female meioses, whereas a tendency to compression was observed almost exclusively in male meioses, for greater-than-or-equal-to 1.5-kb fragments. This impl ies a size- and sex-dependent meiotic instability. Moreover, segregati on analysis supports the hypothesis of a maternal as well as a familia l predisposition for the occurrence of the congenital form. Finally, t his analysis reveals a significant excess of transmitting grandfathers partially accounted for by increased fertility in affected males.