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

Neurology. 2007 Sep 25;69(13):1350-5. doi: 10.1212/01.wnl.0000291779.35643.15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agenesis of Corpus Callosum*
  • Animals
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • DNA Mutational Analysis
  • European Continental Ancestry Group
  • Exons / genetics
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genotype
  • Haplotypes
  • Hereditary Sensory and Autonomic Neuropathies / ethnology
  • Hereditary Sensory and Autonomic Neuropathies / genetics*
  • Hereditary Sensory and Autonomic Neuropathies / physiopathology
  • Humans
  • Inheritance Patterns
  • Male
  • Mutation / genetics*
  • Nervous System Malformations / ethnology
  • Nervous System Malformations / genetics*
  • Nervous System Malformations / physiopathology
  • Oocytes
  • Pedigree
  • Quebec
  • Symporters / chemistry
  • Symporters / genetics*
  • Xenopus laevis

Substances

  • SLC12A6 protein, human
  • Symporters