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 RIS Download
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