The finding that mutations affecting the RING domain impair in vitro ubiquitylation with UBE2D2, have more profoundly decreased RNF213-evoked global ubiquitylation in cells, and have more potent dominant-negative effects argue for a key role of RING-catalyzed ubiquitylation events in MMD pathogenesis. This evidence concerns the gene RNF213 and multiminicore myopathy.