Neil M Renwick, Lev G Goldfarb, Nyamkhishig Sambuughin, Jenny E Hinshaw, Camilo Toro5 and Fyodor A Platonov
Mutations in dynamin-2 are associated with several neuromuscular disorders, including two forms of Charcot- Marie-Tooth disease, axonal CMT2M and intermediate CMTDIB, Centronuclear myopathy ADCNM, Lethal congenital contractures syndrome type 5 LCCS5, and Hereditary spastic paraplegia SPG. Each disorder manifests with muscle weakness and atrophy, however the cause of weakness is due to damage to peripheral nerves in CMT2M and CMTDIB, skeletal muscle degeneration in ADCNM, and disturbances in the upper motor neurons and/or corticospinal tracts in SPG. Pathogenic effects of mutations may result from domain-specific structural and functional disruptions. ADCNMcausing mutations cluster at the interface between the Stalk and Pleckstrin homology domains, whereas CMT-related mutations occur in the part of the Pleckstrin homology domain adjoining the C-terminal Proline/arginine-rich domain. The SPG-associated p.Arg719Trp mutation is uniquely located at the highly conserved hinge region of the Bundlesignaling element, potentially preventing normal assembly of the helical polymer.