DNM2 – Charcot-Marie-Tooth disease, dominant intermediate B

Autosomal dominant variants in DNM2 have been identified in patients with intermediate Charcot-Marie-Tooth neuropathy, type B. A single kindred including a proband and one affected relative harbored a missense variant c.1070C>T (p.Ser357Phe), which co-segregated with a length-dependent sensorimotor neuropathy (2 individuals) (PMID:28971531). No additional unrelated families have been reported.

Functional assays of DNM2 neuropathy-associated mutants demonstrate impaired cytoskeletal and endocytic functions consistent with peripheral nerve dysfunction. Expression of the CMT-linked p.Lys562Glu mutant in U2OS and HeLa cells led to aberrant F-actin clustering, disrupted lamellipodia formation, and decreased co-localization with clathrin-coated pit markers, indicating that specific DNM2 mutations perturb actin dynamics and clathrin-mediated endocytosis in a dominant-negative manner (PMID:27328317).

Key Take-home: Heterozygous DNM2 missense variants cause dominant intermediate CMT neuropathy, but the clinical validity is currently limited by sparse segregation data; however, functional studies support a dominant-negative mechanism and justify inclusion in targeted gene panels.

References

• Neuropathology • 2018 • Phenotype variability and histopathological findings in patients with a novel DNM2 mutation. PMID:28971531
• 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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