Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site
Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site
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.
slc12a6, dna methylation, epigenetics, gene x environment interaction, bipolar disorder, periodic catatonia
458-467
Moser, Dirk
8345e744-f2e2-407c-9f5b-cd6685091923
Ekawardhani, Savira
b70138a5-2e66-471b-adcb-5aa178c81ac6
Kumsta, Robert
88285030-6a7c-4ef1-ba75-b78e09cd2f1e
Palmason, Haukur
56acef25-1d52-45ae-934f-0ceeb67a0c0c
Bock, Christoph
db9a1e5d-09ae-458f-9e86-3a02cdf00bed
Athanassiadou, Zoi
3dcbc34e-339b-47ca-96ae-c12e1d05efb5
Lesch, Klaus-Peter
db534daf-4bb9-4915-9f82-b7f194b3cd3c
Meyer, Jobst
ffc0f18e-a569-454e-b6f6-b2ab7c963c65
7 January 2009
Moser, Dirk
8345e744-f2e2-407c-9f5b-cd6685091923
Ekawardhani, Savira
b70138a5-2e66-471b-adcb-5aa178c81ac6
Kumsta, Robert
88285030-6a7c-4ef1-ba75-b78e09cd2f1e
Palmason, Haukur
56acef25-1d52-45ae-934f-0ceeb67a0c0c
Bock, Christoph
db9a1e5d-09ae-458f-9e86-3a02cdf00bed
Athanassiadou, Zoi
3dcbc34e-339b-47ca-96ae-c12e1d05efb5
Lesch, Klaus-Peter
db534daf-4bb9-4915-9f82-b7f194b3cd3c
Meyer, Jobst
ffc0f18e-a569-454e-b6f6-b2ab7c963c65
Moser, Dirk, Ekawardhani, Savira, Kumsta, Robert, Palmason, Haukur, Bock, Christoph, Athanassiadou, Zoi, Lesch, Klaus-Peter and Meyer, Jobst
(2009)
Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site.
BMC Psychiatry, 34 (2), .
(doi:10.1038/npp.2008.77).
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.
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Published date: 7 January 2009
Keywords:
slc12a6, dna methylation, epigenetics, gene x environment interaction, bipolar disorder, periodic catatonia
Identifiers
Local EPrints ID: 66091
URI: http://eprints.soton.ac.uk/id/eprint/66091
ISSN: 1471-244X
PURE UUID: 63db63ae-284c-4ca2-af8f-0dd8ced7be07
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Date deposited: 28 Apr 2009
Last modified: 13 Mar 2024 18:09
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Author:
Dirk Moser
Author:
Savira Ekawardhani
Author:
Robert Kumsta
Author:
Haukur Palmason
Author:
Christoph Bock
Author:
Zoi Athanassiadou
Author:
Klaus-Peter Lesch
Author:
Jobst Meyer
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