title: Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H.
abstract: Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities, and electrophysiological changes. The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play a key role in regulating signal-transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division. Consistent with these reported functions, expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN. To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT.
authors.affiliation: INSERM U491, Génétique Médicale et Développement, Faculté de Médecine de la Timone, Marseille, France. valerie.delague@medecine.univ-mrs.fr
authors.forename: Valérie
authors.initials: V
authors.lastname: Delague
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquier
authors.forename: Tarik
authors.initials: T
authors.lastname: Hamadouche
authors.forename: Yannick
authors.initials: Y
authors.lastname: Poitelon
authors.forename: Cécile
authors.initials: C
authors.lastname: Baudot
authors.forename: Iréne
authors.initials: I
authors.lastname: Boccaccio
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
authors.forename: Malika
authors.initials: M
authors.lastname: Chaouch
authors.forename: Nora
authors.initials: N
authors.lastname: Kassouri
authors.forename: Rosette
authors.initials: R
authors.lastname: Jabbour
authors.forename: Djamel
authors.initials: D
authors.lastname: Grid
authors.forename: Andre
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Georg
authors.initials: G
authors.lastname: Haase
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D015870:Gene Expression; D005808:Genes, Recessive; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008840:Microfilament Proteins / Q000032:analysis / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020161:Physical Chromosome Mapping; D051381:Rats; D012583:Schwann Cells / Q000201:enzymology; D020741:rho GTP-Binding Proteins / Q000235:genetics
chemical_list: C485164:FGD4 protein, human; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D049452:Green Fluorescent Proteins; D020741:rho GTP-Binding Proteins