title: Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease.
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-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.
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Maher
authors.initials: M
authors.lastname: Noureddine
authors.forename: Marina
authors.initials: M
authors.lastname: Kennerson
authors.forename: Kristien
authors.initials: K
authors.lastname: Verhoeven
authors.forename: Kristl
authors.initials: K
authors.lastname: Claeys
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: John
authors.initials: J
authors.lastname: Merory
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Oliveira
authors.forename: Marcy C
authors.initials: MC
authors.lastname: Speer
authors.forename: Judith E
authors.initials: JE
authors.lastname: Stenger
authors.forename: Gina
authors.initials: G
authors.lastname: Walizada
authors.forename: Danqing
authors.initials: D
authors.lastname: Zhu
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
mesh_terms: 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*
chemical_list: D001798:Blood Proteins; D018076:DNA, Complementary; D010750:Phosphoproteins; C039077:platelet protein P47; D034285:Dynamin II