Instability of myotonic dystrophy CTG trinucleotide repeat

The mutation in myotonic dystrophy (DM) is an expansion of an unstable cytosinethymine-guanine (CTG) trinucleotide repeat located in the 3'untranslated region of the DM protein kinase (DMPK) gene on chromosome 19 q13.3. DM patients have abnormally expanded alleles often with hundreds or even thousands of repeats. Progressive increases of the CTG repeat size in successive generations within a DM pedigree provide a molecular basis for anticipation. The CTG repeat is unstable both in germline and somatic cells in DM patients. However, male germline cells show limited expandability of the repeat during spermatogenesis. This accounts for a lack of paternally transmitted congenital DM cases. In somatic tissues, both intra and inter- tissue heterogeneity of the expanded CTG repeat alleles have been documented. Comparable profiles of inter-tissue repeat variability among DM patients suggest the presence of tissue-specific factors regulating the repeat stability. Longitudinal analyses of the repeat allele distributions over time have shown that the expanded CTG repeat in somatic cells undergo gradual stepwise expansions. This process is ongoing after birth well into the adult life. Studies of DM twins suggest that this type of somatic instability may be regulated by genetic factors. One definite genetic determinant is the repeat length itself. However, as yet unknown cis and trans-acting factors as well as epigenetic factors may also influence the CTG repeat stability. Further dissection of the factors affecting instability using patient- derived tissue samples is complicated by confounding influences of genetic and non-genetic variables. Experimental models including in vivo (transgenic), ex vivo (cell culture) and in vitro models may not only be useful for studying the repeat instability mechanisms but may also be valuable for exploring therapeutic strategies aimed at regulating the repeat instability in DM.