Distal truncation of KCC3 in non-French Canadian HMSN/ACC families

A. Salin-Cantegrel, J. B. Rivière, N. Dupré, F. M. Charron, M. Shekarabi, L. Karéméra, C. Gaspar, J. Horst, M. Tekin, G. Deda, A. Krause, M. M. Lippert, M. A.A.P. Willemsen, R. Jarrar, J. Y. Lapointe, G. A. Rouleau

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1350-1355
Number of pages6
Issue number13
StatePublished - Sep 2007
Externally publishedYes

ASJC Scopus subject areas

  • Clinical Neurology


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