Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations

Abstract

Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two 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. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms.

Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation

“…Based on its membrane tubulation properties and on the muscle phenotype of the amphiphysin Drosophila mutant, BIN1 was proposed to participate in the biogenesis of T-tubules, plasma membrane invaginations forming along with the sarcoplasmic reticulum calcium stores the structural basis of the excitation-contraction coupling machinery in cardiac and skeletal muscles (3,11). BIN1 recessive mutations in CNMs either impair its membrane tubulation properties, its binding to dynamin 2, or the inclusion of a muscle-specific exon encoding a phosphoinositide-binding (PI-binding) domain (6,7,12). DNM2 is a large GTPase involved in membrane fission and endocytosis (13,14).…”

Congenital myopathies: not only a paediatric topic

“…Dominant mutations in BIN1, previously associated with rare, recessively inherited severe CNM cases [42], have also been recently associated with a mild dominant form of CNM [41] ( Figure 2C). Patients typically present later in adulthood with proximal weakness pronounced in the lower limbs, without significant respiratory impairment and only rarely extraocular muscle involvement.…”

“…[39], autosomal-dominant mutations in DNM2 encoding dynamin2 [40] and the BIN1 gene encoding amphiphysin 2 [41], and autosomal-recessive mutations in BIN1 [42], RYR1 encoding the skeletal muscle ryanodine receptor [13], and TTN encoding titin [43]. Most genes implicated to date encode proteins implicated in membrane trafficking (for review, [44]).…”

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

“…Not unexpectedly, these results confirm that changes in the organization of T-tubules lead to functional changes in ECC. Though patients with BIN1 mutations are usually less severely affected than patients with MTM1 mutations and may develop a child or adult onset congenital muscle diseases [133,137], it should be mentioned that the type of mutation plays an important role in the phenotype of the patient and that, contrary to patients who generally do not have heart disease, Bin1 KO mice die shortly after birth because of a hypertrophic ventricular cardiomyopathy.…”