Two novel missense mutations in FGD4/FRABIN cause Charcot-Marie-Tooth type 4H (CMT4H).

By sequencing of the FGD4 coding sequence in a cohort of 101 patients affected by autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT), we have identified two novel missense mutations in FGD4 in two patients from consanguineous descent: p.Arg442His in an Algerian patient and p.Met566Ile in a Lebanese girl. The patients present early onset, slowly progressive CMT, with drastic reduction of nerve conduction velocities. These mutations are the second and third missense mutations characterized in FGD4. They are likely to lead to conformational changes in the PH1 and FYVE domains.

Behavioral and molecular exploration of the AR-CMT2A mouse model Lmna (R298C/R298C).

In 2002, we identified LMNA as the first gene responsible for an autosomal recessive axonal form of Charcot-Marie-Tooth disease, AR-CMT2A. All patients were found to be homozygous for the same mutation in the LMNA gene, p.Arg298Cys. In order to investigate the physiopathological mechanisms underlying AR-CMT2A, we have generated a knock-in mouse model for the Lmna p.Arg298Cys mutation. We have explored these mice through an exhaustive series of behavioral tests and histopathological analyses, but were not able to find any peripheral nerve phenotype, even at 18 months of age. Interestingly at the molecular level, however, we detect a downregulation of the Lmna gene in all tissues tested from the homozygous knock-in mouse Lmna (R298C/R298C) (skeletal muscle, heart, peripheral nerve, spinal cord and cerebral trunk). Importantly, we further reveal a significant upregulation of Pmp22, specifically in the sciatic nerves of Lmna (R298C/R298C) mice. These results indicate that, despite the absence of a perceptible phenotype, abnormalities exist in the peripheral nerves of Lmna (R298C/R298C) mice that are absent from other tissues. Although the mechanisms leading to deregulation of Pmp22 in Lmna (R298C/R298C) mice are still unclear, our results support a relation between Lmna and Pmp22 and constitute a first step toward understanding AR-CMT2A physiopathology.

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

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.