G.P.38: Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations

Abstract

Centronuclear myopathies (CNM) are congenital muscle disorders characterized by an increased number of muscle fibers with central nuclei. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive CNM with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). However, the genetic basis of the disease is not known for all cases. Here we characterize a novel CNM entity. We established a homogeneous cohort of nine patients from five families with dominant CNM without mutations in DNM2. All patients presented with a mildly progressive adult-onset myopathy and had similar histological and ultrastructural features involving type I fiber predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all five families: two missense mutations in the N-terminal amphipathic helix, and three single nucleotide deletions involving the loss of the stop codon. Amphiphysin 2 (encoded by BIN1) induces membrane tubulation and is implicated in excitation-contraction coupling (ECC) at the T-tubules. We confirmed mutation segregation with the disease in the dominant families, and we complemented the molecular diagnosis by functional analyses. Both missense mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Additional immunolabeling experiments revealed abnormal central accumulation of dynamin 2 and caveolin-3, and general membrane alterations of the triad, the sarcolemma, and the basal lamina. In conclusion, we identified BIN1 as a novel gene for dominant adult-onset CNM. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant CNM and that both disorders involve different pathomechanisms.