Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease.
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.
Züchner
Stephan
S
Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Noureddine
Maher
M
Kennerson
Marina
M
Verhoeven
Kristien
K
Claeys
Kristl
K
De Jonghe
Peter
P
Merory
John
J
Oliveira
Sofia A
SA
Speer
Marcy C
MC
Stenger
Judith E
JE
Walizada
Gina
G
Zhu
Danqing
D
Pericak-Vance
Margaret A
MA
Nicholson
Garth
G
Timmerman
Vincent
V
Vance
Jeffery M
JM
D000818:Animals; D001798:Blood Proteins / Q000737:chemistry / Q000235:genetics*; D015153:Blotting, Western; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D003001:Cloning, Molecular; D018076:DNA, Complementary; D034285:Dynamin II / Q000737:chemistry / Q000235:genetics*; D005799:Genes, Dominant; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics*
D001798:Blood Proteins; D018076:DNA, Complementary; D010750:Phosphoproteins; C039077:platelet protein P47; D034285:Dynamin II