BIN1 – Autosomal Dominant Centronuclear Myopathy

Autosomal dominant centronuclear myopathy (AD CNM) is a congenital muscle disorder characterized by muscle weakness, nuclear centralization within myofibers and exercise intolerance. Pathogenic variants in BIN1 (amphiphysin-2) have been identified in multiple unrelated families, establishing BIN1 as a dominant CNM gene. Clinical features range from childhood-onset with pronounced myalgia and exercise intolerance to adult-onset progressive weakness without facial involvement.

Genetic studies have identified heterozygous BIN1 variants in 9 probands from 5 families (PMID:25260562) and in a multigenerational Dutch kindred (PMID:29103045). Segregation analysis confirms autosomal dominant inheritance and co-segregation of rare missense and stop-loss alleles with disease. The variant spectrum includes N-terminal amphipathic helix substitutions (e.g., c.53T>A (p.Val18Glu)) and C-terminal stop-loss mutations, supporting a dominant-negative or gain-of-function mechanism.

Most AD CNM variants cluster within the BAR domain or terminate upstream of the SH3 domain. The recurrent c.53T>A (p.Val18Glu) change impairs membrane-tubulation activity in vitro (PMID:29103045). In the adult cohort, N-terminal helix mutations markedly reduce BIN1-mediated membrane deformation, and stop-loss alleles produce stable proteins that aberrantly accumulate at the triad, disrupting T-tubule organization (PMID:25260562).

Functional assays across multiple studies demonstrate that pathogenic BIN1 variants compromise membrane remodeling: patient myofibers show mislocalized amphiphysin-2 and disorganized triads, and zebrafish bin1 knockdown recapitulates centronuclear pathology with defective excitation–contraction coupling. Rescue experiments in BIN1-deficient models restore tubulation, underscoring the mechanistic link between BIN1 dysfunction and CNM.

No conflicting reports have challenged BIN1’s role in dominant CNM. The weight of genetic segregation, variant clustering, and concordant functional data supports a strong gene–disease association. Further cohorts and long-term follow-up will solidify genotype–phenotype correlations, but current evidence justifies inclusion of BIN1 in AD CNM diagnostic panels.

Key Take-home: Heterozygous BIN1 variants cause autosomal dominant CNM via impaired membrane tubulation, and BIN1 genetic testing is critical for accurate diagnosis and genetic counseling.

References

• Journal of neuromuscular diseases • 2017 • Dominant Centronuclear Myopathy with Early Childhood Onset due to a Novel Mutation in BIN1. PMID:29103045
• Brain : a journal of neurology • 2014 • Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations. PMID:25260562

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