HYPERMUTABLE MYOTONIC-DYSTROPHY CTG REPEATS IN TRANSGENIC MICE

Myotonic dystrophy (DM) is one of a growing number of inherited human disorders associated with the expansion of triplet repeat DNA sequence s(1). Expanded alleles are highly unstable in both the germline and so ma, accounting in large part for the unusual genetics of this disorder , its phenotypic variability and probably, the progressive nature of t he symptoms(2-7) However, the molecular mechanisms and the genetic fac tors modulating repeat stability in DM and the other human disorders a ssociated with expanded repeats are not well understood. To provide a model system in which the turnover of triplet repeats could be studied throughout mammalian development, we have generated five transgenic m ouse lines incorporating expanded CTG/CAG arrays derived from the huma n DM locus. Transgene analysis has revealed germline hypermutability, including expansions, deletions and parent-of-origin effects, somatic and early embryonic instability and segregation distortion. Mutational differences between lines and sexes demonstrate that stability, as in humans, is modulated by as yet unidentified cis and trans acting gene tic elements.