Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin

The syntrophins are a family of structurally related proteins that contain multiple protein interaction motifs, Syntrophins associate directly with dy strophin, the product of the Duchenne muscular dystrophy locus, and its hom ologues, We have generated alpha-syntrophin null mice by targeted gene disr uption to test the function of this association. The alpha-Syn(-/-) mice sh ow no evidence of myopathy, despite reduced levels of alpha-dystrobrevin-2, . Neuronal nitric oxide synthase, a component of the dystrophin protein com plex, is absent from the sarcolemma of the alpha-Syn(-/-) mice, even where other syntrophin isoforms are present. alpha-Syn(-/-) neuromuscular junctio ns have undetectable levels of postsynaptic utrophin and reduced levels of acetylcholine receptor and acetylcholinesterase. The mutant junctions have shallow nerve gutters, abnormal distributions of acetylcholine receptors, a nd postjunctional folds that are generally less organized and have fewer op enings to the synaptic cleft than controls. Thus, alpha-syntrophin has an i mportant role in synapse formation and in the organization of utrophin, ace tylcholine receptor, and acetyl cholinesterase at the neuromuscular synapse .