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+–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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Change history
16 October 2002
This was incorrect in AOP version but corrected in print. Changed the size of the bands in this subsection as stated in the note.
Notes
Note: In the AOP version of this article, the sizes of the bands from the mutant KCC3Q protein were stated incorrectly in the Results subsection titled "Immunoblotting and immunofluorescence microscopy." The sizes of the bands were actually ∼90 kD and 115 kD, rather than ∼90kD and 120 kD as stated. The full-text online version of the article has been corrected and the article will appear correctly in an upcoming print issue.
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Acknowledgements
We would like to thank all the families who participated in this study; the Vanderbilt Ingram Cancer Center Transgenic/ES Cell Shared Resource Core for expertise and help; R. Desai for technical assistance; the Tennessee Mouse Genome Consortium Neurohistology Core; and C. Laberge for providing DNA from control subjects from the Saguenay region. This work was supported by La Fondation des jumelles Coudés, the Canadian Institute for Health Research and the US National Institutes of Health. D.B.M. was also supported by a VA Advanced Research Career Development Award.
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Web Movie A
Open-field analysis of KCC3 wildtype (+/+) and knockout (-/-) mice. Whereas the wildtype mouse moves freely in the cage without disrupting the corncob substrate, the knockout mouse slips and leaves wide tracks in the bedding.
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Howard, H., Mount, D., Rochefort, D. et al. The K–Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet 32, 384–392 (2002). https://doi.org/10.1038/ng1002
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DOI: https://doi.org/10.1038/ng1002
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