Dynamin 2 (DNM2) Lys558 in Australian & Belgian families with neutropenia

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Letter from 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 disease

Stephan Züchner1, 2, Maher Noureddine1, Marina Kennerson3, 4,

Kristien Verhoeven4, Kristl Claeys5, 6, De Jonghe5, 6,

Merory7, Sofia A Oliveira1, Marcy C Speer1, Judith E Stenger1,

Walizada3, Danqing Zhu3, Margaret A Pericak-Vance1, Garth Nicholson3,

4, Timmerman5 & Jeffery M Vance1

1 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, 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 & #8722;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.