Chemical reversal of the RNA gain of function in myotonic dystrophy

摘要

Myotonic dystrophy type 1 (DM1) is one of a number of microsatellite expansion diseases in which the causative mutation is an aberrant expansion of a 3-nt repeat (1). The DM1 mutation was identified in 1992, and by 2001 it was established that the primary cause of pathogenesis is toxicity of the repeat-containing RNA transcribed from the expanded allele. One mechanism by which the RNA induces pathogenesis is through direct binding and sequestration of the RNA binding protein, muscle-blind-like 1 (MBNL1). MBNL1 regulates a subset of alternative splicing events, and its depletion from the nucle-oplasm results in misregulation of these events, causing features of the disease (2). In this issue of PNAS, Warf et al.