Nature Genetics
37, 289 - 294 (2005)
Published online: 30 January 2005; | doi:10.1038/ng1514
Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth diseaseStephan Züchner1, 2, Maher Noureddine1, Marina Kennerson3, 4, Kristien Verhoeven4, Kristl Claeys5, 6, Peter De Jonghe5, 6, John Merory7, Sofia A Oliveira1, Marcy C Speer1, Judith E Stenger1, Gina Walizada3, Danqing Zhu3, Margaret A Pericak-Vance1, Garth Nicholson3, 4, Vincent Timmerman5
& Jeffery M Vance11
Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA. 2
Department of Neuropathology, University Hospital, RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. 3
Northcott Neuroscience Laboratory, ANZAC Research Institute, New South Wales, Australia. 4
Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia. 5
Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium. 6
Division of Neurology, University Hospital Antwerpen, Antwerpen, Belgium. 7
Department of Neurology, Heidelberg Repatriation Hospital, West Heidelberg, Victoria 3081, Australia. 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  3/4 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.
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