Dystrophia myotonia: why focus on foci?

ABSTRACT

Dystrophia myotonia type 1 (DM1; Steinert's disease; myotonic dystrophy) is an autosomal dominant disorder due to a large CTG expansion in the 3'-untranslated region (UTR) of the DM protein kinase (DMPK) gene. Transcription of this gene yields a long CUGn-containing mutant (mut) RNA, in which clinical disease is associated with repeats of n=100-5000. Phenomenologically, the expression of mut RNA is correlated with the morphologic observation of ribonucleoprotein precipitates ('foci') in the nuclei of DMPK-expressing cells. The prevailing view is that the identification of proteins in these foci is the sine qua non of protein-mut RNA interactions. In this viewpoint, I contend that this is an unwarranted inference that falls short in explaining published data. A new model of mut RNA-protein interactions is proposed with distinct binding properties for soluble and insoluble (focus) mut RNA that accommodate these data without exclusions.