SH3BP2 deficiency in skeletal muscle leads to neuromuscular junction abnormalities and decreased muscle strength

Assembly and stabilization of a high density of acetylcholine receptors (AChRs) at the neuromuscular junction postsynaptic domain is fundamental for proper synaptic transmission. Here, we report the identification of a scaffold protein, SH3BP2, that exhibits polyvalent and direct interactions with the dystrophin-glycoprotein complex (DGC) and AChR pentamers. Loss-of-function experiments in cultured myotubes revealed that SH3BP2 promotes formation of AChR assemblies in muscle cells. Similarly, muscle-specific deletion of SH3BP2 in mice impairs AChR clustering during embryonic development and causes multiple neuromuscular junction morphological and ultrastructural abnormalities in adult animals. Mutant mice also exhibit defects in synaptic transmission, muscle strength, and general fitness. Our study identifies a novel role for SH3BP2 in modulating the neuromuscular junction in skeletal muscles.