a1 Department of Pharmacology, University of Cologne, Cologne, Germany
a2 University of Wuerzburg, Department of Child and Adolescent Psychiatry, Julius-Maximilians-University, Würzburg, Germany
a3 Department of Child and Adolescent Psychiatry, Technical University Aachen, Aachen, Germany
a4 Department of Child and Adolescent Psychiatry, University Freiburg, Freiburg, Germany
a5 Department of Child and Adolescent Psychiatry, Philipps-University Marburg, Marburg, Germany
Obsessive–compulsive disorder (OCD) is a disease of complex aetiology with a marked genetic component. Impact of the serotonergic system has been reported but the contribution of additional transmitter systems to the pathogenesis seems likely. The extraneuronal monoamine transporter, EMT (SLC22A3), is implicated in non-neuronal termination of noradrenergic signalling in the central nervous system and a candidate gene for a variety of neuropsychiatric disorders. We conducted a case-control study of 84 Caucasian children and adolescents with OCD according to DSM-IV criteria, and healthy adults by comprehensive sequencing of the EMT gene. Additionally, targeted genotype analysis was done with patient–parent trios. Known polymorphisms and frequent haplotypes were not associated with OCD in the present sample. Transmission disequilibrium test was negative for the presumptive cryptic splice site 1233G>A polymorphism. However, we identified two novel independent mutations exclusively in affected patients. A thus far unknown –106/107delAG mutation was detected in three male patients of unaffected parents but was not prevalent in 204 healthy subjects (p=0.024). In a luciferase reporter assay the mutant allele conferred increased promoter activity by 36%. Furthermore, we describe the first non-synonymous substitution in the EMT gene, Met370Ile, in a family of affected female members that co-segregated with the disease. The residue exhibits a high degree of inter-species conservation. Heterologous expression of mutant cDNA revealed a 40% decline of transport capacity for norepinephrine. Rare mutations in the EMT gene suggest a causative or modulating role in genetic subtypes of OCD.
(Received September 02 2006)
(Reviewed November 22 2006)
(Revised February 18 2007)
(Accepted March 07 2007)
(Online publication May 04 2007)
c1 Address for correspondence: A. Lazar, M.D., Department of Pharmacology, University Hospital, University of Cologne, Gleueler Str. 24, 50931 Köln, Germany. Tel.: +49-221-478-4196 Fax: +49-221-478-5022 E-mail: [email protected]
* These authors contributed equally to this work.