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

Nat Genet. 2002 Nov;32(3):384-92. doi: 10.1038/ng1002. Epub 2002 Oct 7.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Agenesis of Corpus Callosum*
  • Animals
  • Blotting, Southern
  • Brain / pathology
  • Canada
  • Chromosomes, Human, Pair 15
  • Corpus Callosum / embryology
  • 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 / genetics*
  • Phenotype
  • Polymorphism, Genetic
  • Recombination, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Sodium-Potassium-Chloride Symporters / genetics
  • Spinal Cord / pathology
  • Symporters / genetics*
  • Symporters / physiology*
  • Time Factors
  • Xenopus


  • SLC12A6 protein, human
  • Slc12a6 protein, mouse
  • Sodium-Potassium-Chloride Symporters
  • Symporters

Associated data

  • GENBANK/AF105366
  • GENBANK/AF116242
  • GENBANK/AF314931
  • GENBANK/AF314932
  • GENBANK/AF314933
  • GENBANK/AF314934
  • GENBANK/AF314935
  • GENBANK/AF314936
  • GENBANK/AF314937
  • GENBANK/AF314938
  • GENBANK/AF314939
  • GENBANK/AF314940
  • GENBANK/AF314941
  • GENBANK/AF314942
  • GENBANK/AF314943
  • GENBANK/AF314944
  • GENBANK/AF314945
  • GENBANK/AF314946
  • GENBANK/AF314947
  • GENBANK/AF314948
  • GENBANK/AF314949
  • GENBANK/AF314950
  • GENBANK/AF314951
  • GENBANK/AF314952
  • GENBANK/AF314953
  • GENBANK/AF314954
  • GENBANK/AF314955
  • GENBANK/AF314956
  • GENBANK/AQ345102
  • RefSeq/NT_024680