Mutations in the Frabin gene can cause a variable phenotype and lead to protein

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Mutations in the Frabin gene can cause a variable phenotype and lead to protein

truncation;

R. Paudel\ M. Launi!, M. Lunn\ S. Hammans2 , H. Katifi2 , H. Houldenl and M.M.

Reilly

TMRC Centre for Neuromuscular diseases, The National Hospital for Neurology and

Neurosurgery and Department of Molecular Neurosciences, The Institute of

Neurology, London, UK; 2 Wessex Neurological

Centre Southampton General Hospital, Southampton UK

Charcot MaIie Tooth disease (CMT) is a clinically and genetically heterogeneous

group of disorders characterized by progressive distal muscle weakness and

atrophy, foot deformities and sensory loss. Autosomal recessive (AR) CMT is

clinically and genetically heterogeneous. The number of genes for AR CMT has

rapidly increased over the last few yeas.

The AR CMT phenotype is usually more severe and has an eaIlier onset than

autosomal dominant (AD) CMT, there are often additional clinical features such

as scoliosis and cranial neuropathies. The frequency of AR CMT is much less than

AD overall (except in countries

with a high rate of consanguinity), although this may change as the number of AR

genetic causes are identified De Sandre-Giovannoli et al identified the CMT4H

locus on chromosome 12p1121-q13 II in two large consanguineous families.

Clinically these families had severe childhood onset demyelinating CMT with

frequent focally folded myelin seen on sural nerve biopsy. The CMT4H gene was

recently identified and five mutations in six AR

CMT families were reported in the Frabin gene. This gene is a GDP/GTP nucleotide

exchange factor specific to Cdc42, a member of the Rho family of small GTP

binding proteins. We screened the entire Frabin gene in a cohort of 12 AR CMT

patients and identified a homozygous R275X mutation in a family from Northern

Ireland. This faImily had

a mild slowly progressive phenotype although nerve conduction studies still

showed severe demyelination. Examination ofmRNA from lymphoblasts showed that

this stop mutation caused very little non-sense mediated mRNA decay and the

predominant mRNA species was

the mutant form that translates into a truncated protein This work extends the

understanding of the pathogenesis of CMT4H caused by Fr3bin mutations.