Dynamin 2 mutations cause dominant intermediate CMT

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Abstract from Nat Genet. 2005 Jan 30

Mutations in the pleckstrin homology domain of dynamin 2 cause dominant

intermediate Charcot-Marie-Tooth disease.

Zuchner S, Noureddine M, Kennerson M, Verhoeven K, Claeys K, Jonghe PD, Merory

J, Oliveira SA, Speer MC, Stenger JE, Walizada G, Zhu D, Pericak-Vance MA,

Nicholson G, Timmerman V, Vance JM.

[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.

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.

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