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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.
