© 1992 Oxford University Press
RESEARCH-ARTICLE |
Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype
Department of Anatomy, Charing Cross Westminster Medical School St Dunstan's Road, London W6 8RF, UK 1OYKS, Department of Medical Genetics SF-90220 Oulu, Finland 2Department of Human Genetics, University of Leipzig Chemnitzer StraBe 50/A5, D-(0)7039 Leipzig, Germany 3Institute of Human Genetics and Medical Biology, Martin Luther University Halle-Wittenberg School of Medicine Karl-Liebknecht-StraBe 11, D-(0)4020 Halle, Germany 4Neurological Clinic, University of Leipzig Chemnitzer StraBe 50/A2, D-(0)7039 Leipzig, Germany 5Department of Biochemistry and Molecular Genetics, St Mary's Hospital Medical School, Imperial College London W2 1PG, UK
*To whom correspondence should be addressed
Received August 3, 1992; Revised August 27, 1992; Accepted August 27, 1992
Myotonic dystrophy (DM) is associated with the expansion and instability of a trinucleotide (CTG) repeat in a sequence encoding a cAMP-dependent protein kinase. The normal copy number of 5 – 35 repeats is exceeded in DM patients, with the size of the expansion broadly correlating with the severity of symptoms experienced. In most families reported, the unstable DNA sequence has increased in size on transmission to affected offspring, thereby providing a molecular explanation for the phenomenon of anticipation in DM, i.e. an increase in the severity of symptoms associated with an earlier age at onset of the disease in successive generations of a family. Here we present the first reported case of a family where the transmission of the affected chromosome from father to son is accompained by a reduction in the size of the triplet expansion, such that it falls within the normal range. As the son remains asymptomatic, this type of molecular event may provide an explanation for the incomplete penetrance of the disease phenotype reported for this disorder. The implications for genetic counselling of DM families and the mechanistic considerations of the trinucleotide instability are discussed.
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