CMT 4H/CMT 1: A novel Frabin (FGD4) nonsense mutation p.R275X associated with ph

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Neurology. 2009 Feb 17;72(7):617-620.

A novel Frabin (FGD4) nonsense mutation p.R275X associated with

phenotypic variability in CMT4H.

Houlden H, Hammans S, Katifi H, Reilly MM.

Institute of Neurology, Queen Square, London, UK WC1N 3BG

BACKGROUND: Charcot Marie Tooth (CMT) disease is a heterogeneous

group of inherited peripheral motor and sensory neuropathies. CMT4H

is an early onset autosomal recessive demyelinating neuropathy. The

locus responsible for CMT4H was assigned to chromosome 12p11.21-

q13.11 by homozygosity mapping and mutations in the Frabin gene (FGD4

Rho GDP/GTP exchange factor) were subsequently identified in six

families.

METHODS: We sequenced the Frabin gene in a cohort of 12 UK CMT

families with clinically defined autosomal recessive demyelinating

neuropathy.

RESULTS: We identified a novel homozygous Frabin p.R275X mutation in

a family from Northern Ireland. The two affected cases in this family

had a very slowly progressive neuropathy with both cases remaining

ambulant into middle age. Examination of mRNA from lymphoblasts

showed that this stop mutation caused very little nonsense mediated

mRNA decay and the predominant mRNA species was the mutant form that

is likely to be translated into a truncated protein.

CONCLUSIONS: This work extends the understanding of the pathogenesis

of Frabin mutation-associated Charcot Marie Tooth (CMT) 4H and

suggests that mutations in Frabin should also be considered in

ambulant adults with CMT1.