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- Title
The K–Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.
- Authors
Howard, Heidi C.; Mount, David B.; Rochefort, Daniel; Byun, Nellie; Dupré, Nicolas; Lu, Jianming; Fan, Xuemo; Song, Luyan; Rivière, Jean-Baptiste; Prévost, Claude; Horst, Jürgen; Simonati, Alessandro; Lemcke, Beate; Welch, Rick; England, Roger; Zhan, Frank Q.; Mercado, Adriana; Siesser, William B.; George, Alfred L.; McDonald, Michael P.
- 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[SUP+]-CI[SUP-] transporter KCC3 and maps within the ACCPN candidate region, was screened for mutations in individuais 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 (2436deIG, 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 Sic12a6 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.
- Subjects
NEUROPATHY; CORPUS callosum
- Publication
Nature Genetics, 2002, Vol 32, Issue 3, p384
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng1002