Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease.

Published

Journal Article

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of peripheral neuropathies. Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC. We refined the locus associated with DI-CMTB on chromosome 19p12-13.2 to 4.2 Mb in three unrelated families with CMT originating from Australia, Belgium and North America. After screening candidate genes, we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus. In transiently transfected cell lines, mutations of DNM2 substantially diminish binding of DNM2 to membranes by altering the conformation of the beta3/beta4 loop of the pleckstrin homology domain. Additionally, in the Australian and Belgian pedigrees, which carry two different mutations affecting the same amino acid, Lys558, CMT cosegregated with neutropenia, which has not previously been associated with CMT neuropathies.

Full Text

Duke Authors

Cited Authors

  • Züchner, S; Noureddine, M; Kennerson, M; Verhoeven, K; Claeys, K; De Jonghe, P; Merory, J; Oliveira, SA; Speer, MC; Stenger, JE; Walizada, G; Zhu, D; Pericak-Vance, MA; Nicholson, G; Timmerman, V; Vance, JM

Published Date

  • March 2005

Published In

Volume / Issue

  • 37 / 3

Start / End Page

  • 289 - 294

PubMed ID

  • 15731758

Pubmed Central ID

  • 15731758

International Standard Serial Number (ISSN)

  • 1061-4036

Digital Object Identifier (DOI)

  • 10.1038/ng1514

Language

  • eng

Conference Location

  • United States