Meyer Jobst, Johannssen Kirsten, Freitag Christine M, Schraut Kerstin, Teuber Isabel, Hahner Astrid, Mainhardt Christian, Mössner Rainald, Volz Hans-Peter, Wienker Thomas F, McKeane Darleen, Stephan Dietrich A, Rouleau Guy, Reif Andreas, Lesch Klaus-Peter
Clinical and Molecular Psychobiology, Department of Psychiatry and Psychotherapy, University of Wuerzburg, Germany.
Int J Neuropsychopharmacol. 2005 Dec;8(4):495-504. doi: 10.1017/S1461145705005821. Epub 2005 Aug 5.
Recessive mutations of the potassium chloride co-transporter 3 gene ( SLC12A6 , KCC3 ) cause severe peripheral neuropathy frequently associated with agenesis of the corpus callosum and psychoses (ACCPN). SLC12A6 is localized on chromosome 15q14, a region where linkage to schizophrenia and bipolar disorder has previously been shown. Mutation analysis of SLC12A6 was carried out by direct sequencing of PCR-generated DNA fragments in two affected members of a multiplex family, and three non-affected individuals. A case-control study was performed to assess association of variants with bipolar disorder and schizophrenia in a large sample. Several variants including two rare single nucleotide polymorphisms (G/A, G/A) in the promoter and 5'-UTR, and a thymidine insertion in intron 4 were found. The two G variants and the insertion variant were co-inherited with chromosome 15-related schizophrenia in a large family that strongly supports the region on chromosome 15q14-15 between markers D15S144 and D15S132. Furthermore, they are in linkage disequilibrium with each other, and significantly associated with bipolar disorder in a case-control study. Our data strongly suggest that rare variants of SLC12A6 may represent risk factors for bipolar disorder.
