AR CMT: Peripheral Nerve Demyelination Caused by a Mutant Rho GTPase Guanine Nuc

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Am J Hum Genet. 2007 Jul;81(1):158-64.

Peripheral Nerve Demyelination Caused by a Mutant Rho GTPase Guanine

Nucleotide Exchange Factor, Frabin/FGD4.

Stendel C, Roos A, Deconinck T, Pereira J, Castagner F, Niemann A,

Kirschner J, Korinthenberg R, Ketelsen UP, Battaloglu E, Parman Y,

Nicholson G, Ouvrier R, Seeger J, Jonghe PD, Weis J, Kruttgen A,

Rudnik-Schoneborn S, Bergmann C, Suter U, Zerres K, Timmerman V,

Relvas JB, Senderek J.

Institute of Cell Biology, Zurich, Switzerland.

GTPases of the Rho subfamily are widely involved in the myelination

of the vertebrate nervous system. Rho GTPase activity is temporally

and spatially regulated by a set of specific guanine nucleotide

exchange factors (GEFs). Here, we report that disruption of

frabin/FGD4, a GEF for the Rho GTPase cell-division cycle 42

(Cdc42), causes peripheral nerve demyelination in patients with

autosomal recessive Charcot-Marie-Tooth (CMT) neuropathy. These

data, together with the ability of frabin to induce Cdc42-mediated

cell-shape changes in transfected Schwann cells, suggest that Rho

GTPase signaling is essential for proper myelination of the

peripheral nervous system.