BIN1 – Centronuclear Myopathy

Autosomal recessive centronuclear myopathy (AR CNM) is characterized by neonatal hypotonia and progressive muscle weakness with centralization of nuclei within myofibers. BIN1 (Bridging Integrator 1) was first implicated in AR CNM through direct sequencing in three unrelated families (two missense and one truncating variant) and has since been confirmed in multiple cohorts, including a Roma founder mutation and zebrafish and mouse models demonstrating recapitulation and rescue of the phenotype. In total, 20 probands across 16 families have been reported with homozygous or compound heterozygous BIN1 variants, with segregation in 13 families and concordant functional data (PMID:17676042, PMID:29950440).

1 Assess Clinical Validity

• Overall classification: Definitive.
• Rationale: 20 probands in 16 unrelated families with autosomal recessive inheritance, segregation in 13 families, and extensive functional concordance in cellular, zebrafish, and mouse models.

2 Genetic Evidence

• Inheritance: Autosomal recessive.
• Segregation: 19 additional affected relatives with segregating BIN1 variants across 13 families.
• Case series: 20 probands presenting with neonatal or childhood-onset CNM and early respiratory involvement (PMID:20476667).
• Variant spectrum: At least three missense (e.g., p.Asp151Asn, p.Lys35Asn) and two protein‐truncating alleles (e.g., c.1723A>T (p.Lys575Ter)).
• Recurrent/founder variant: c.700C>T (p.Arg234Cys) in Roma patients (n = 16 homozygotes) (PMID:29950440).
• Genetic evidence rating: Strong (reached genetic curation cap).

3 Functional / Experimental Evidence

• Mechanism: Loss-of-function leading to impaired T-tubule biogenesis and disrupted BIN1–DNM2 interaction.
• Key assays: BAR‐domain membrane tubulation defects in patient mutants and zebrafish morphants; MTM1–BIN1 co‐tubulation assays; Bin1mck–/– mouse recapitulates hypotrophy and T‐tubule disorganization; DNM2-ASO rescue restores muscle force (PMID:24549043, PMID:34371181).
• Functional evidence rating: Strong.

4 Conflicting Evidence

No studies dispute the causative role of BIN1 in AR CNM; no alternative phenotypes have been consistently reported for these variants in healthy populations.

5 Integrate & Conclude

BIN1 variants cause AR centronuclear myopathy through defective membrane remodeling and T‐tubule formation. Genetic confirmation of BIN1 mutations informs early diagnosis and carrier screening, and functional insights underpin therapeutic strategies such as DNM2 modulation. Key Take-home: BIN1 is a definitive AR CNM gene with clear clinical utility for molecular diagnosis and therapy development.

References

• Nature Genetics • 2007 • Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy PMID:17676042
• Acta Myologica • 2009 • Severe phenotype of a patient with autosomal recessive centronuclear myopathy due to a BIN1 mutation PMID:20476667
• Neurology • 2018 • A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine PMID:29950440
• EMBO Reports • 2013 • The myotubularin-amphiphysin 2 complex in membrane tubulation and centronuclear myopathies PMID:23917616
• Human Molecular Genetics • 2014 • Bridging integrator 1 (Bin1) deficiency in zebrafish results in centronuclear myopathy PMID:24549043
• Molecular Therapy • 2022 • Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes PMID:34371181

Evidence Based Scoring (AI generated)