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

Stephan Züchner, Maher Noureddine, Marina Kennerson, Kristien Verhoeven, Kristl Claeys, Peter De Jonghe, John Merory, Sofia A. Oliveira, Marcy C. Speer, Judith E. Stenger, Gina Walizada, Danqing Zhu, Margaret A. Pericak-Vance, Garth Nicholson, Vincent Timmerman, Jeffery M. Vance

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Abstract

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-CMTA1, DI-CMTB2 and DI-CMTC3. 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 apparatus4. In transiently transfected cell lines, mutations of DNM2 substantially diminish binding of DNM2 to membranes by altering the conformation of the β3/β4 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.

Original languageEnglish (US)
Pages (from-to)289-294
Number of pages6
JournalNature genetics
Volume37
Issue number3
DOIs
StatePublished - Dec 9 2005

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ASJC Scopus subject areas

  • Genetics

Cite this

Züchner, S., Noureddine, M., Kennerson, M., Verhoeven, K., Claeys, K., De Jonghe, P., Merory, J., Oliveira, S. A., Speer, M. C., Stenger, J. E., Walizada, G., Zhu, D., Pericak-Vance, M. A., Nicholson, G., Timmerman, V., & Vance, J. M. (2005). Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nature genetics, 37(3), 289-294. https://doi.org/10.1038/ng1514