| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
From the Centre for the Study of Brain Diseases (A.S.-C., J.-B.R., M.S., L.K., C.G., G.A.R.), CHUM Research Centre–Notre-Dame Hospital and the University of Montreal, Québec; Department of Neurological Sciences (N.D.), CHAUQ-Enfant-Jesus, Quebec City; Department of Physics (F.M.C., J.-Y.L.), Université de Montreal, Québec, Canada; Institut fur Humangenetik (J.H.), Universitatsklinikum Munster, Germany; Pediatric Molecular Genetics Department (M.T., G.D.), Ankara University, School of Medicine, Turkey; Department of Human Genetics (A.K., M.M.L.), National Health Laboratory Service and University of Witwatersand, South Africa; Department of Paediatric Neurology (M.A.A.P.W.), University Medical Centre, St. Radboud, Nijmegen, The Netherlands; and Gillette Children’s Specialty Health Care (R.J.), St. Paul, MN.
Address correspondence and reprint requests to Dr Rouleau, Centre for the Study of Brain Diseases, CHUM Research Centre–Notre-Dame Hospital and the University of Montreal, Montreal, Québec, Canada guy.rouleau{at}umontreal.ca
Background: Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a severe and progressive autosomal recessive polyneuropathy. Mutations in the potassium-chloride cotransporter 3 gene (KCC3) were identified as responsible for HMSN/ACC in the French Canadian (FC) population. In the present study, the authors were interested in finding new mutations in non-FC populations, assessing the activity of mutant proteins and refining genotype-phenotype correlations.
Methods: The authors screened KCC3 for mutations using direct sequencing in six non-FC HMSN/ACC families. They then assessed the functionality of the most common mutant protein using a flux assay in Xenopus laevis oocytes.
Results: The authors identified mutations in exon 22 of KCC3: a novel mutation (del + 2994-3003; E1015X) in one family, as well as a known mutation (3031C
T; R1011X) found in five unrelated families and associated with two different haplotypes. The function of the cotransporter was abolished, although a limited amount of mutant proteins were correctly localized at the membrane.
Conclusions: KCC3 mutations in exon 22 constitute a recurrent mutation site for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), regardless of ethnic origin, and are the most common cause of HMSN/ACC in the non–French Canadian (FC) families analyzed so far. Therefore, for genetic analysis, exon 22 screening should be prioritized in non-FC populations. Finally, the R1011X mutation leads to the abrogation of KCC3’s function in Xenopus laevis oocytes, likely due to impaired transit of the cotransporter.
GLOSSARY: ANOVA = analysis of variance; CTD = C-terminal domain; FC = French Canadian population; HMSN/ACC = hereditary motor and sensory neuropathy with agenesis of the corpus callosum; KCC3 = potassium-chloride cotransporter 3; mut = mutated sequence; NGS = normal goat serum; RVD = regulatory volume decrease; WT = wild type sequence.
Supplemental data at www.neurology.org
*These authors contributed equally to this work.
Supported by the Canadian Institutes of Health Research and the Fondation des Jumelles Coudé.
Disclosure: The authors report no conflicts of interest.
Received October 25, 2006. Accepted in final form April 19, 2007.
This article has been cited by other articles:
|
|
 |
|
  A. Salin-Cantegrel, M. Shekarabi, S. Holbert, P. Dion, D. Rochefort, J. Laganiere, S. Dacal, P. Hince, L. Karemera, C. Gaspar, et al. HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3 Hum. Mol. Genet., September 1, 2008; 17(17): 2703 - 2711. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
