Nature Genetics
32, 384 - 392 (2002)
Published online: 7 October 2002; Corrected online: 16 October 2002 | doi:10.1038/ng1002
There is a Corrigendum (December 2002) associated with this Article.
The K−Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosumHeidi C. Howard1, 13, David B. Mount2, 3, 13, Daniel Rochefort1, Nellie Byun4, Nicolas Dupré1, Jianming Lu4, Xuemo Fan5, Luyan Song3, Jean-Baptiste Rivière1, Claude Prévost6, Jürgen Horst7, Alessandro Simonati8, Beate Lemcke8, Rick Welch3, Roger England4, Frank Q. Zhan4, Adriana Mercado2, 3, William B. Siesser9, Alfred L. George Jr3, Michael P. McDonald9, 10, 11, Jean-Pierre Bouchard12, Jean Mathieu6, Eric Delpire4, 9, 11
& Guy A. Rouleau11
Centre for Research in Neuroscience, McGill University and the Montreal General Hospital Research Institute, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada. 2
Renal Division, West Roxbury VA Medical Center and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. 3
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 4
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 5
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 6
Complexe hospitalier de la Sagamie, Chicoutimi, Quebec, Canada. 7
Institut für Humangenetik, Universität Münster, Münster, Germany. 8
Department of Neurological and Visual Sciences, Section of Neurology, University of Verona, Verona, Italy. 9
Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 10
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 11
John F. Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 12
Department of Neurology, Hôpital de l'Enfant Jesus, Quebec, Quebec, Canada. 13
These authors contributed equally to this work
Correspondence should be addressed to Eric Delpire eric.delpire@vanderbilt.edu or Guy A. Rouleau guy.rouleau@mcgill.caPeripheral 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.
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