Variant interrupted DMPK alleles: implications in the pathogenesis and molecular diagnosis of myotonic dystrophy type 1 (DM1)

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease caused by a pathological CTG repeat expansion in the 3’-untranslated region (UTR) of the DMPK gene on chromosome 19q13.2-q13.3. Although the CTG repeat tract is usually uninterrupted in both healthy and expanded alleles of DM1 patients, in the last years, pathological variants expansion containing unstable CCG, CTC and CGG sequence interruptions have been reported in rare instances. Complex variant repeats were identified at the 3’-end of the CTG array of DM1 patients of different origin, with an estimated prevalence of 3-5% of cases. The presence of interruptions within an otherwise homogeneous tract of repeats has been associated with a number of TREDs including FRAXA, SCA1, SCA2 and FRDA. In general, repeat interruptions lead to a stabilizing effect because of their ability to disrupt the formation of unusual DNA structures formed by “pure” repetitive sequences. The analysis of DM1 families reported so far in literature, straightens this hypothesis, indicating that interruptions in the CTG repeated tract render the expanded allele more stable, or could even predispose to its contraction during intergenerational transmissions. However, the phenotypical consequences of the interrupted alleles on DM1 patients is still controversial, leading to complex neurological phenotypes or mild later-onset forms. Changes in the sequence of the CTG array could modify the higher structure of the DMPK expanded transcripts and their interactions with RNA binding proteins. By influencing the nucleosome assembly across the repeat, interruptions can also modulate chromatin structure, which in turn may affect the cellular RNA metabolism. The identification of complex DMPK expansions has also important practical consequences for DM1 molecular genetic testing where they can lead to false negative conclusions. Moreover, because of the great uncertainty about the phenotypic consequences of interrupted DMPK alleles and their level of somatic mosaicism, the prediction of the clinical outcome is difficult in carriers of these alleles in DM1 genetic counseling.