The University of Southampton
University of Southampton Institutional Repository

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
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
1471-244X
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
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), 458-467. (doi:10.1038/npp.2008.77).

Record type: Article

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.

This record has no associated files available for download.

More information

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

Catalogue record

Date deposited: 28 Apr 2009
Last modified: 13 Mar 2024 18:09

Export record

Altmetrics

Contributors

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×