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The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.

Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) is a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. ACCPN is transmitted in an autosomal recessive fashion and is found at a high frequency in the province of Quebec, Canada. ACCPN has been previously mapped to chromosome 15q. The gene SLC12A6 (solute carrier family 12, member 6), which encodes the K+-Cl- transporter KCC3 and maps within the ACCPN candidate region, was screened for mutations in individuals with ACCPN. Four distinct protein-truncating mutations were found: two in the French Canadian population and two in non-French Canadian families. The functional consequence of the predominant French Canadian mutation (2436delG, Thr813fsX813) was examined by heterologous expression of wildtype and mutant KCC3 in Xenopus laevis oocytes; the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional. Mice generated with a targeted deletion of Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor gating deficit, similar to the human disease. Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for SLC12A6 in the development and maintenance of the nervous system.

Pubmed ID: 12368912


  • Howard HC
  • Mount DB
  • Rochefort D
  • Byun N
  • Dupré N
  • Lu J
  • Fan X
  • Song L
  • Rivière JB
  • Prévost C
  • Horst J
  • Simonati A
  • Lemcke B
  • Welch R
  • England R
  • Zhan FQ
  • Mercado A
  • Siesser WB
  • George AL
  • McDonald MP
  • Bouchard JP
  • Mathieu J
  • Delpire E
  • Rouleau GA


Nature genetics

Publication Data

November 31, 2002

Associated Grants


Mesh Terms

  • Agenesis of Corpus Callosum
  • Animals
  • Blotting, Southern
  • Brain
  • Canada
  • Chromosomes, Human, Pair 15
  • Corpus Callosum
  • Exons
  • Gene Deletion
  • Genes, Recessive
  • Haplotypes
  • Homozygote
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Models, Genetic
  • Molecular Sequence Data
  • Mutation
  • Open Reading Frames
  • Peripheral Nervous System Diseases
  • Phenotype
  • Polymorphism, Genetic
  • Recombination, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Sodium-Potassium-Chloride Symporters
  • Spinal Cord
  • Symporters
  • Time Factors
  • Xenopus