A putative role of ribonuclear inclusions and MBNL1 in the impairment of gallbladder smooth muscle contractility with cholelithiasis in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by expansion of unstable trinucleotide (CTG) repeats at 3' untranslated region of the DMPK gene on chromosome 19q13.3. Mutant transcripts are retained in muscle nuclei as ribonuclear inclusions and interact with RNA-binding proteins, such as muscleblind-like protein 1 (MBNL1), leading to a reduction in their activity. The reduced MBNL1 activity has been associated to skeletal and cardiac muscle dysfunction. However, other organs and systems may be involved. It has been reported that 25-50% of DM1 patients have abdominal symptoms due to cholelithiasis or gallstones. Since impaired gallbladder motility plays an important role in gallstones formation, we have analyzed by FISH combined with MBNL1-immunofluorescence, the gallbladder obtained from a woman affected by DM1 who required a cholecystectomy at the age of 30. Gallbladders obtained from two no-DM1 subjects have been used as controls. Ribonuclear inclusions and MBNL1 foci accumulate and colocalize in nuclei of DM1 gallbladder smooth muscle cells. On the contrary, no ribonuclear inclusions are detectable in cell nuclei of control gallbladders and MBNL1 is uniformly distributed in smooth muscle cell nuclei. These results suggest that nuclear accumulation of MBNL1 and ribonuclear inclusions may have a direct adverse effect on gallbladder smooth muscle contractility and thus contribute to gallstones formation in DM1 patients.