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Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy NATURE STRUCTURAL & MOLECULAR BIOLOGY Rau, F., Freyermuth, F., Fugier, C., Villemin, J., Fischer, M., Jost, B., Dembele, D., Gourdon, G., Nicole, A., Duboc, D., Wahbi, K., Day, J. W., Fujimura, H., Takahashi, M. P., Auboeuf, D., Dreumont, N., Furling, D., Charlet-Berguerand, N. 2011; 18 (7): 840-U120

Abstract

Myotonic dystrophy is an RNA gain-of-function disease caused by expanded CUG or CCUG repeats, which sequester the RNA binding protein MBNL1. Here we describe a newly discovered function for MBNL1 as a regulator of pre-miR-1 biogenesis and find that miR-1 processing is altered in heart samples from people with myotonic dystrophy. MBNL1 binds to a UGC motif located within the loop of pre-miR-1 and competes for the binding of LIN28, which promotes pre-miR-1 uridylation by ZCCHC11 (TUT4) and blocks Dicer processing. As a consequence of miR-1 loss, expression of GJA1 (connexin 43) and CACNA1C (Cav1.2), which are targets of miR-1, is increased in both DM1- and DM2-affected hearts. CACNA1C and GJA1 encode the main calcium- and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons.

View details for DOI 10.1038/nsmb.2067

View details for Web of Science ID 000292507500013

View details for PubMedID 21685920