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

Abstract

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.

• Authors: Heidi C Howard, David B Mount, Daniel Rochefort, Nellie Byun, Nicolas Dupré, Jianming Lu, Xuemo Fan, Luyan Song, Jean-Baptiste Rivière, Claude Prévost, Jürgen Horst, Alessandro Simonati, Beate Lemcke, Rick Welch, Roger England, Frank Q Zhan, Adriana Mercado, William B Siesser, Alfred L George Jr, Michael P McDonald, Jean-Pierre Bouchard, Jean Mathieu, Eric Delpire, Guy A Rouleau
• Journal: Nature genetics (Nat Genet) Vol. 32 Issue 3 Pg. 384-92 (Nov 2002) ISSN: 1061-4036 [Print] United States
• PMID: 12368912 (Publication Type: Comparative Study, Journal Article, 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.)

Chemical References

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

Topics

• 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, physiology)
• Time Factors
• Xenopus