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.
D061085:Agenesis of Corpus Callosum; D000818:Animals; D015139:Blotting, Southern; D001921:Brain / Q000473:pathology; D002170:Canada; D002884:Chromosomes, Human, Pair 15; D003337:Corpus Callosum / Q000196:embryology; D005091:Exons; D017353:Gene Deletion; D005808:Genes, Recessive; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology; D027981:Symporters / Q000235:genetics* / Q000502:physiology*; D013997:Time Factors; D014981:Xenopus; D000096922:K Cl- Cotransporters
D028021:Sodium-Potassium-Chloride Symporters; D027981:Symporters; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters; C492280:Slc12a6 protein, mouse