SOMATIC HETEROGENEITY OF THE CTG REPEAT IN MYOTONIC-DYSTROPHY IS AGE AND SIZE-DEPENDENT

The most common form of adult muscular dystrophy, myotonic dystrophy ( DM), is caused by the abnormal expansion of the CTG repeat, located in the 3' UTR of the DM gene. The expanded-CTG allele often presents as a diffused band on Southern blot analysis, suggesting somatic mosaicis m. In order to study the somatic instability of the CTG repeat, we hav e investigated the dynamics of the size heterogeneity of the CTG expan sion. Size heterogeneity is shown as a smear on Southern blot and is m easured by the midpeak-width ratio of the expanded allele to the norma l sized allele. The ratio is also corrected for compression in the hig her-molecular-weight region. It is found that the size heterogeneity o f the expanded-CTG repeats, of 173 DM patients, correlates well with t he age of the patient (r = .81, P much less than .001). The older pati ents show larger size variation. This correlation is independent of th e sex of either the patient or the transmitting parent. The size heter ogeneity of the expansion, based on age groups, is also dependent on t he size of the expanded trinucleotide repeat. However, obvious size he terogeneity is not observed in congenital cases, regardless of the siz e of expansion. Comparison of individual patient samples collected at two different times has confirmed that the degree of size heterogeneit y increases with age and has revealed a subtle but definite upward shi ft in the size of the expanded-CTG allele. The progression of the CTG repeat toward larger expansion with age is further confirmed by small- pool PCR assay that resolved the heterogeneous fragments into discrete bands. This report, for the first time, documents the quantitative me asurement of size heterogeneity of CTG-repeat expansion and shows the increasing size and size heterogeneity with age.