DNM2 – Centronuclear Myopathy

Autosomal dominant centronuclear myopathy (CNM) is a congenital myopathy characterized by muscle fibers containing centrally located nuclei and radial sarcoplasmic strands. The DNM2 gene (HGNC:2974) encodes dynamin-2, a large GTPase essential for membrane trafficking and T-tubule maintenance in skeletal muscle. Heterozygous DNM2 mutations cluster in the PH and middle domains and disrupt membrane tubulation, leading to myofiber disorganization and progressive weakness (PMID:23374900, PMID:17932957).

DNM2-related CNM follows an autosomal dominant inheritance pattern with multiple family reports. A novel c.1840G>A (p.Asp614Asn) variant segregated with disease in 4 additional affected relatives in a Polish kindred (PMID:23374900). In a large cohort study encompassing 100 families, 18 distinct DNM2 mutations were described, including nine novel variants, establishing clear genotype-phenotype correlations (PMID:22396310). These data meet strong ClinGen criteria for gene-disease validity.

The variant spectrum is predominantly missense, with hotspots at residues Arg369 and Ser619. Recurrent mutations include c.1105C>T (p.Arg369Trp) in multiple pedigrees (PMID:22924779) and c.1939C>G (p.Pro647Ala) associated with late onset and unusual necklace fibers (PMID:25633151). No deep-intronic or hypomorphic alleles have been consistently reported in DNM2-CNM.

Clinically, DNM2-CNM presents across a broad age range from neonatal hypotonia to adult distal weakness. Common features include early-onset lower limb muscle weakness, ptosis, ophthalmoparesis, facial weakness, and occasional myotonic discharges (HP:0001324, HP:0000508, HP:0000597) (PMID:24366529, PMID:17932957). Muscle MRI reveals preferential involvement of tibialis anterior and soleus, with radially arranged sarcoplasmic strands on biopsy.

Functional studies demonstrate that CNM-linked DNM2 mutants form abnormally stable polymers with hyperactive GTPase activity, impair BIN1-mediated tubulation, and fragment T-tubules in cell and animal models (PMID:20529869, PMID:24135484). In AAV-mediated mouse studies, expression of R465W dynamin-2 recapitulated CNM histopathology and weakness, while reducing DNM2 levels via shRNA or antisense oligonucleotides rescued muscle structure and function (PMID:21514436, PMID:30291191).

Some DNM2 variants cause Charcot-Marie-Tooth neuropathy rather than CNM, reflecting tissue-specific effects; for example, K562E impairs neuromuscular junction transmission without triad disruption (PMID:21762456). No studies have refuted the DNM2–CNM association.

Integration of genetic and experimental data supports a Strong level of clinical validity. DNM2-CNM arises from dominant gain-of-function mutations that disrupt membrane dynamics in muscle fibers. Genetic testing for DNM2 should be prioritized in autosomal dominant or sporadic CNM, and DNM2 reduction represents a promising therapeutic strategy.

References

• Neuromuscular Disorders • 2013 • A novel mutation in the DNM2 gene impairs dynamin 2 localization in skeletal muscle of a patient with late onset centronuclear myopathy. PMID:23374900
• Annals of Neurology • 2007 • Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset. PMID:17932957
• Human Mutation • 2012 • Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. PMID:22396310
• Ophthalmic Genetics • 2013 • Histopathologic changes in the extraocular muscle in centronuclear myopathy with a Dynamin 2 mutation. PMID:22924779
• Neuromuscular Disorders • 2015 • A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres. PMID:25633151
• The Journal of Biological Chemistry • 2010 • Dynamin 2 mutants linked to centronuclear myopathies form abnormally stable polymers. PMID:20529869
• Disease Models & Mechanisms • 2014 • The myopathy-causing mutation DNM2-S619L leads to defective tubulation in vitro and in developing zebrafish. PMID:24135484
• The American Journal of Pathology • 2011 • Increased expression of wild-type or a centronuclear myopathy mutant of dynamin 2 in skeletal muscle of adult mice leads to structural defects and muscle weakness. PMID:21514436
• Proceedings of the National Academy of Sciences • 2018 • Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy. PMID:30291191
• Traffic • 2011 • Common membrane trafficking defects of disease-associated dynamin 2 mutations. PMID:21762456

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