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.

The Atypical Guanine-Nucleotide Exchange Factor, Dock7, Negatively Regulates Schwann Cell Differentiation and Myelination

“…Our conclusions may be supported by the observation that Dock7 in sciatic nerves is developmentally downregulated; it expresses strongly in earlier stages but very weakly thereafter, whereas Rho GTPases Rac1/Cdc42 exhibit stable levels of expression throughout sciatic nerve development. Schwann cells also contain other GEFs for Rho GTPases (Verhoeven et al, 2003;Hempstead, 2005;Delague et al, 2007;Stendel et al, 2007). The diversity of GEFs and/or Rho GTPase expression profiles may be one of the reasons for the phenotypic differences between Dock7 shRNA transgenic mice and Rac1 or Cdc42 knock-out mice (Benninger et al, 2007;Chan, 2007;Nodari et al, 2007).…”

“…A number of mutations of the fgd4 (also called frabin) gene are found in peripheral demyelinating Charcot-Marie-Tooth (CMT) neuropathy type 4H (CMT4H), which causes myelin outfoldings and deformed scoliosis (Delague et al, 2007;Stendel et al, 2007;Fabrizi et al, 2009;Houlden et al, 2009). FGD4 is a Dbl family GEF specific for Cdc42.…”

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

“…There are phosphoinositide-binding domains in several proteins linked to CMT, including dynamin2 (ref. 17), KIF1Bb 18 , neurofilament (NEFL) 19 , Pleckstrin homology (PH) domain containing, family G member 5 (PLEKHG5) 20 and Frabin/ FGD 21,22 . Notably, mutations in the PI(4,5)P 2 -binding domains of dynamin2 (ref.…”

FGD2, a CDC42-specific Exchange Factor Expressed by Antigen-presenting Cells, Localizes to Early Endosomes and Active Membrane Ruffles

“…FGD3 and FGD4 have also been shown to modulate the actin cytoskeleton and to be Cdc42-specific exchange factors (18,19). Interestingly, mutations of Fgd4 (Frabin) are associated with the peripheral nerve disease, Charcot-Marie-Tooth disease (20,21). Although annotated in genetic data bases, Fgd5 and Fgd6 are so far uncharacterized.…”