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Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site.

Abstract
The human potassium-chloride co-transporter 3 (KCC3, SLC12A6) is involved in cell proliferation and in electro-neutral movement of ions across the cell membrane. The gene (SLC12A6) is located on chromosome 15q14, a region that has previously shown linkage with bipolar disorder, schizophrenia, rolandic epilepsy, idiopathic generalized epilepsy, autism and attention deficit/hyperactivity disorder. Furthermore, recessively inherited mutations of SLC12A6 cause Andermann syndrome, characterized by agenesis of the corpus callosum, which is associated with peripheral neuropathy and psychoses. Recently, we have demonstrated the association of two G/A promoter polymorphisms of SLC12A6 with bipolar disorder in a case-control study, and familial segregation of the rare variants as well as a trend toward association with schizophrenia. To investigate functional consequences of these polymorphisms, lymphocyte DNA was extracted, bisulfite modified, and subsequently sequenced. To investigate SLC12A6 promoter activity, various promoter constructs were generated and analyzed by luciferase reporter gene assays. We provide evidence that the G- allele showed a significant reduction of reporter gene expression. In human lymphocytes, the allele harboring the rare upstream G nucleotide was found to be methylated at the adjacent C position, possibly accountable for tissue-specific reduction in gene expression in vivo. Here we demonstrate functionality of an SNP associated with psychiatric disease and our results may represent a functional link between genetic variation and an epigenetic modification.
AuthorsDirk Moser, Savira Ekawardhani, Robert Kumsta, Haukur Palmason, Christoph Bock, Zoi Athanassiadou, Klaus-Peter Lesch, Jobst Meyer
JournalNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 34 Issue 2 Pg. 458-67 (Jan 2009) ISSN: 1740-634X [Electronic] England
PMID18536702 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • SLC12A6 protein, human
  • Symporters
Topics
  • Bipolar Disorder (genetics)
  • Cell Line
  • CpG Islands (physiology)
  • DNA Methylation
  • Epigenesis, Genetic
  • Genes, Reporter
  • Humans
  • Lymphocytes (chemistry, physiology)
  • Molecular Sequence Data
  • Plasmids
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Sequence Analysis, Protein
  • Symporters (chemistry, genetics)

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