DNM2 – Autosomal Dominant Centronuclear Myopathy

Autosomal dominant centronuclear myopathy (ADCNM) is a congenital skeletal muscle disorder characterized by neonatal or infantile hypotonia, delayed motor milestones, and progressive muscle weakness. ADCNM is caused by heterozygous missense mutations in the dynamin 2 gene (DNM2), a ubiquitously expressed GTPase involved in endocytosis and membrane trafficking. Muscle biopsies from affected individuals consistently show central nuclei with radial sarcoplasmic strands and preserved peripheral nerve function, supporting a primary myopathic mechanism (PMID:16227997).

Genetic evidence includes 23 probands from 11 unrelated families with ADCNM harboring recurrent or de novo DNM2 missense variants, most clustering in the pleckstrin homology domain (PMID:16227997; PMID:20227276). The inheritance is autosomal dominant, with segregation in multiplex families (mother–daughter pair) and multiple de novo cases. A representative recurrent variant is c.1852G>A (p.Ala618Thr) identified in both familial and sporadic presentations (PMID:16227997).

Functional studies demonstrate that ADCNM-associated DNM2 mutants exhibit hyperactive GTPase activity, form abnormally stable oligomers resistant to disassembly, and disrupt triad and T-tubule architecture in muscle fibers (PMID:20529869). Knock-in mouse models expressing the common p.Arg465Trp mutation recapitulate muscle atrophy, nuclear mislocalization, and reduced muscle force (PMID:30291191). Moreover, DNM2 reduction via antisense oligonucleotides or AAV-shRNA rescues histopathological and functional defects in vivo, affirming a gain-of-function disease mechanism (PMID:30291191).

No significant conflicting reports have been published disputing the DNM2–ADCNM link. Available data consistently support a dominant gain-of-function effect in skeletal muscle, distinct from the hypomorphic mutations causing DNM2-associated Charcot–Marie–Tooth neuropathy.

In summary, heterozygous missense mutations in DNM2 cause ADCNM via a hyperactive GTPase mechanism leading to T-tubule and triad dysfunction. Clinical testing for DNM2 variants should be considered in patients with early hypotonia, muscle weakness, and characteristic biopsy features. Targeted reduction of DNM2 represents a promising therapeutic approach.

Key Take-home: ADCNM patients with DNM2 mutations benefit from molecular diagnosis and may be candidates for DNM2-directed therapies.

References

• Nature Genetics • 2005 • Mutations in dynamin 2 cause dominant centronuclear myopathy. PMID:16227997
• Neuromuscular Disorders • 2010 • Expanding the clinical, pathological and MRI phenotype of DNM2-related centronuclear myopathy. PMID:20227276
• The Journal of Biological Chemistry • 2010 • Dynamin 2 mutants linked to centronuclear myopathies form abnormally stable polymers. PMID:20529869
• Proceedings of the National Academy of Sciences • 2018 • Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy. PMID:30291191

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