A novel Frabin (FGD4) nonsense mutation p.R275X associated with phenotypic variability in CMT4H.

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.