DNM2 – Dynamin 2-related Charcot-Marie-Tooth Disease

Autosomal dominant mutations in the dynamin 2 gene (DNM2; HGNC:2974) have been robustly associated with Charcot-Marie-Tooth disease (CMT; MONDO:0015626). CMT is a genetically heterogeneous peripheral neuropathy characterized by distal muscle weakness, sensory loss, and variable electrophysiological features.

Genetic evidence stems from five unrelated families harboring pleckstrin homology domain variants. In three autosomal dominant intermediate CMT pedigrees (Australian, Belgian, North American), unique heterozygous DNM2 variants were identified, including c.1684A>G (p.Lys562Glu), which cosegregated with CMT and neutropenia in two families (PMID:15731758). Two further pedigrees with purely axonal CMT harbored novel missense mutations in the same domain, including c.1609G>A (p.Gly537Ser), demonstrating segregation in kindreds without muscle involvement (PMID:17636067).

Overall at least seven affected probands and segregation across five families, combined with consistent autosomal dominant inheritance, support a Strong gene–disease association. Reported DNM2 variant classes include missense substitutions and small in-frame deletions clustering in the pleckstrin homology domain. The recurrent c.1684A>G (p.Lys562Glu) variant exemplifies pathogenic alteration of a key membrane-binding residue.

Segregation analysis across these pedigrees demonstrated concordant transmission in multiple affected relatives (≥5 additional individuals), reinforcing evidence for dominant inheritance and pathogenicity of DNM2 variants.

Functional assays of CMT-associated DNM2 mutants reveal impaired membrane association and altered actin dynamics. PH domain substitutions diminish membrane binding in transfected cells, disrupting clathrin-independent endocytosis and actin remodeling (PMID:15731758; PMID:27328317). These concordant cellular phenotypes align with peripheral nerve dysfunction in patients.

No conflicting reports have been documented for DNM2–CMT, and all identified variants display consistent autosomal dominant segregation and functional disruption of dynamin 2 activity.

In summary, autosomal dominant DNM2 variants in the pleckstrin homology domain cause CMT via a dominant-negative or hypomorphic mechanism affecting membrane trafficking in peripheral nerves. Genetic testing for DNM2 should be considered in AD CMT patients, especially those with intermediate conduction velocities or neutropenia, to inform diagnosis and family counseling.

References

• Nature genetics • 2005 • Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. PMID:15731758
• Neurology • 2007 • Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth disease. PMID:17636067
• Neuroscience letters • 2016 • Expression of a dynamin 2 mutant associated with Charcot-Marie-Tooth disease leads to aberrant actin dynamics and lamellipodia formation. PMID:27328317

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