Synthetic oligonucleotides containing GC-rich triplet sequences were used in a scanning strategy to identify unstable genetic sequences at the myotonic dystrophy (DM) locus. A highly polymorphic GCT repeat was identified and found to be unstable, with an increased number of repeats occurring in DM patients. In the case of severe congenital DM, the paternal triplet allele was inherited unaltered while the maternal, DM-associated allele was unstable. These studies suggest that the mutational mechanism leading to DM is triplet amplification, similar to that occurring in the fragile X syndrome. The triplet repeat sequence is within a gene (to be referred to as myotonin-protein kinase), which has a sequence similar to protein kinases.

An unstable expansion of the CTG repeat in the 3' untranslated region of the myotonin protein kinase (MT-PK) gene is the mutation specific for myotonic dystrophy (DM). To examine somatic stability of the repeat, we studied tissue variability of the repeat size. In five DM patients, the restriction fragment containing the repeat region was substantially larger in skeletal muscle than in peripheral blood leukocytes (PBL). In addition, one normal subject showed a size discrepancy in one of the normal alleles by one repeat on the polymerase chain reaction analysis. In most DM patients, the repeat size of native PBL differed from the transformed lymphoblastoid cells after passages. In contrast, various tissues from a congenital DM patient showed a similar size of the expanded repeat, including the transformed lymphoblastoid cells. We conclude that somatic instability of the CTG repeat may cause substantial tissue variability of the CTG repeat size in adult-onset DM, providing a potential mechanism for the variable pleiotropism.

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