Somatic instability of CTG repeat in myotonic dystrophy

Abstract

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.

Characteristics of dynamic mutation in Japanese myotonic dystrophy

“…The characteristics of DM dynamic mutation have been reported in English (Harley et al, 1992b(Harley et al, , 1993, French (Lavedan et al, 1993), Spanish (Cobo et al, 1993), Canadian (Hunter et al, 1992Tsilfidis et aL, 1992;Barcelo et al, 1993). Australian (Mulley el al., 1993), and American people (Ashizawa et aL, , 1993(Ashizawa et aL, , 1994aRedman et al, 1993). We previously showed that CTG expansion was also detected in Japanese DM .…”

Complex patterns of male germline instability and somatic mosaicism in myotonic dystrophy type 1

“…Whilst in the main such observations usually correlate quite well with the observed clinical anticipation, quite a high proportion of cases have been demonstrated apparent reductions in the allele length not associated with an improvement of the patients clinical symptoms. 10 Since it is known that the expanded CTG repeat is highly unstable in both somatic tissues 11,12 and in the male germline, 13,14 some account of these factors needs to be made in interpreting measured intergenerational differences, given that the somatic changes in repeat length could influence the interpretation of intergenerational changes. Detailed studies of somatic mosaicism have revealed that it is tissue specific, [11][12][13] biased toward further expansion and continuous throughout the life of an individual.…”

“…10 Since it is known that the expanded CTG repeat is highly unstable in both somatic tissues 11,12 and in the male germline, 13,14 some account of these factors needs to be made in interpreting measured intergenerational differences, given that the somatic changes in repeat length could influence the interpretation of intergenerational changes. Detailed studies of somatic mosaicism have revealed that it is tissue specific, [11][12][13] biased toward further expansion and continuous throughout the life of an individual. [14][15][16][17] Clearly, progressive somatic mosaicism has implications for interpreting intergenerational transmissions based on the analysis of average allele sizes in the blood of parent and offspring.…”

Myotonic Dystrophy Associated with Insulinoma.

“…The size of expansion correlates to a reasonable degree with the clinical symptoms not only within a given family but also within each internal organ of one body (9)(10)(11)(12)(13). Disturbed glucose tolerance is a well-knowncomplication of the disease showing elevated plasma insulin levels and a normal response to exogenous insulin (2,4).…”