Document Detail

Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H.
MedLine Citation:
PMID:  17564959     Owner:  NLM     Status:  MEDLINE    
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.
Valérie Delague; Arnaud Jacquier; Tarik Hamadouche; Yannick Poitelon; Cécile Baudot; Iréne Boccaccio; Eliane Chouery; Malika Chaouch; Nora Kassouri; Rosette Jabbour; Djamel Grid; Andre Mégarbané; Georg Haase; Nicolas Lévy
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-05-15
Journal Detail:
Title:  American journal of human genetics     Volume:  81     ISSN:  0002-9297     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-06-13     Completed Date:  2007-09-04     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1-16     Citation Subset:  IM    
INSERM U491, Génétique Médicale et Développement, Faculté de Médecine de la Timone, Marseille, France.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/AA305646;  AK057294;  AY367054;  AY368076;  BAE90450;  BC045552;  CAK11116;  CN643653; RefSeq/NM_139234;  NM_139241;  NP_001023039;  NP_004454;  NP_149077;  NP_631978;  NP_640334;  NP_640356;  NP_775829;  XP_416365;  XP_520721;  XP_543741
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MeSH Terms
Amino Acid Sequence
Charcot-Marie-Tooth Disease / genetics*
Chromosomes, Human, Pair 12 / genetics
Gene Expression
Genes, Recessive*
Green Fluorescent Proteins / analysis,  genetics
Guanine Nucleotide Exchange Factors / genetics*
Microfilament Proteins / analysis,  genetics*
Molecular Sequence Data
Physical Chromosome Mapping
Schwann Cells / enzymology
rho GTP-Binding Proteins / genetics
Reg. No./Substance:
0/FGD4 protein, human; 0/Guanine Nucleotide Exchange Factors; 0/Microfilament Proteins; 147336-22-9/Green Fluorescent Proteins; EC GTP-Binding Proteins

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