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Nat Genet November 1, 2002; 32 (3): 384-92.

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

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 .

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
Article link: Nat Genet

Species referenced: Xenopus
Genes referenced: slc12a6
GO keywords: chloride ion homeostasis [+]

Disease Ontology terms: hereditary motor and sensory neuropathy with agenesis of the corpus callosum