HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Houlden, H. Articles by Reilly, M. M. Search for Related Content PubMed PubMed Citation Articles by Houlden, H. Articles by Reilly, M. M. Related Collections All Neuromuscular Disease Peripheral neuropathy Gene expression studies All Genetics

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

From MRC Centre for Neuromuscular Disease and Department of Molecular Neurosciences (H.H., M.M.R.), The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, Queen Square, London; and Wessex Neurological Centre (S.H., H.K.), Southampton General Hospital, UK.

Address correspondence and reprint requests to Dr. Henry Houlden, Institute of Neurology, Queen Square, London, UK WC1N 3BG h.houlden{at}ion.ucl.ac.uk

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.

Abbreviations: AR = autosomal recessive; CMT = Charcot Marie Tooth; MCV = motor conduction velocity; MRC = Medical Research Council; NMD = nonsense mediated mRNA decay.

Supported by Medical Research Council's clinician Scientist Fellowship (H.H.) as well as other grants, the Muscular Dystrophy Campaign, and the Brain Research Trust. This work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centers funding scheme.

Disclosure: The authors report no disclosures.

Received August 11, 2008. Accepted in final form November 12, 2008.