Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H

Am J Hum Genet. 2007 Jul;81(1):1-16. doi: 10.1086/518428. Epub 2007 May 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Charcot-Marie-Tooth Disease / genetics*
  • Chromosomes, Human, Pair 12 / genetics
  • Gene Expression
  • Genes, Recessive*
  • Green Fluorescent Proteins / analysis
  • Green Fluorescent Proteins / genetics
  • Guanine Nucleotide Exchange Factors / genetics*
  • Humans
  • Microfilament Proteins / analysis
  • Microfilament Proteins / genetics*
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Physical Chromosome Mapping
  • Rats
  • Schwann Cells / enzymology
  • rho GTP-Binding Proteins / genetics


  • FGD4 protein, human
  • Guanine Nucleotide Exchange Factors
  • Microfilament Proteins
  • Green Fluorescent Proteins
  • rho GTP-Binding Proteins

Associated data

  • GENBANK/AA305646
  • GENBANK/AK057294
  • GENBANK/AY367054
  • GENBANK/AY368076
  • GENBANK/BAE90450
  • GENBANK/BC045552
  • GENBANK/CAK11116
  • GENBANK/CN643653
  • RefSeq/NM_139234
  • RefSeq/NM_139241
  • RefSeq/NP_001023039
  • RefSeq/NP_004454
  • RefSeq/NP_149077
  • RefSeq/NP_631978
  • RefSeq/NP_640334
  • RefSeq/NP_640356
  • RefSeq/NP_775829
  • RefSeq/XP_416365
  • RefSeq/XP_520721
  • RefSeq/XP_543741