Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy

Abstract

Centronuclear myopathies are characterized by muscle weakness and abnormal centralization of nuclei in muscle fibers not secondary to regeneration. The severe neonatal X-linked form (myotubular myopathy) is due to mutations in the phosphoinositide phosphatase myotubularin (MTM1), whereas mutations in dynamin 2 (DNM2) have been found in some autosomal dominant cases. By direct sequencing of functional candidate genes, we identified homozygous mutations in amphiphysin 2 (BIN1) in three families with autosomal recessive inheritance. Two missense mutations affecting the BAR (Bin1/amphiphysin/RVS167) domain disrupt its membrane tubulation properties in transfected cells, and a partial truncation of the C-terminal SH3 domain abrogates the interaction with DNM2 and its recruitment to the membrane tubules. Our results suggest that mutations in BIN1 cause centronuclear myopathy by interfering with remodeling of T tubules and/or endocytic membranes, and that the functional interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei.

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

“…1 Several genes are reported to be associated with CNM; these include MTM1 in the X-linked form, 3,4 DNM2 and MTMR14 in the autosomal dominant forms, [4][5][6] BIN1 and RYR1 associated with the autosomal recessive forms. 4,[7][8][9] X-linked myotubular myopathy (XLMTM; MIM 310400) has a prevalence of approximately 1/50 000 males and is characterized by severe hypotonia present at birth and inability to maintain sustained spontaneous respiration. 10 Different authors have proposed that patients be classified according to their phenotype, as: (i) severecharacteristic facial features, markedly delayed motor milestones and requiring prolonged ventilatory support (412 h); (ii) moderatemore rapid acquirement of motor milestones and independent respiration for 412 h per day; (iii) mild -motor milestones slightly delayed and independent spontaneous respiratory function achieved after the neonatal period.…”

Clinical utility gene card for: Centronuclear and myotubular myopathies

“…[21][22][23] BIN1: Five homozygous mutations have been reported in patients with CNM2 including three missense changes (p.K35N, p.D151N and p.R154Q) and two nonsense mutations (p.Q573X and K575X). [24][25][26] RYR1: To date, RYR1-related CNM has been mainly associated with compound heterozygosity for recessive RYR1 mutations, typically a missense mutation and a mutation predicted to reduce the amount of the functional RyR1 protein. 3,4 The mutational spectrum includes missense mutations, frame-shifting small insertions and deletions, and splice-altering mutations.…”

Noncentrosomal microtubules in C. elegans epithelia

“…Although mainly known for its role in endocytosis (Pant et al, 2009), mutations in Amphiphysin-2/CeAMPH-1 also induce a nuclear mis-positioning and aberrant nuclear shapes in all species. In human, mutations in Amhiphysin-2 (also known as BIN1) have been associated with centronuclear myopathy, a pathology in which muscle nuclei are found in the middle of the cells rather than at their periphery (Nicot et al, 2007). In C. elegans amph-1 mutants have irregularly spaced nuclei in their seam cells (D'Alessandro et al, 2015).…”