title: Novel mutations of the extraneuronal monoamine transporter gene in children and adolescents with obsessive-compulsive disorder.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Cologne, Cologne, Germany. andreas.lazar@medizin.uni-koeln.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Lazar
authors.forename: Susanne
authors.initials: S
authors.lastname: Walitza
authors.forename: Alexander
authors.initials: A
authors.lastname: Jetter
authors.forename: Manfred
authors.initials: M
authors.lastname: Gerlach
authors.forename: Andreas
authors.initials: A
authors.lastname: Warnke
authors.forename: Beate
authors.initials: B
authors.lastname: Herpertz-Dahlmann
authors.forename: Dirk
authors.initials: D
authors.lastname: Gründemann
authors.forename: Gundula
authors.initials: G
authors.lastname: Grimberg
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Helmut
authors.initials: H
authors.lastname: Remschmidt
authors.forename: Christoph
authors.initials: C
authors.lastname: Wewetzer
authors.forename: Edgar
authors.initials: E
authors.lastname: Schömig
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000502:physiology; D009771:Obsessive-Compulsive Disorder / Q000235:genetics* / Q000523:psychology; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D010375:Pedigree; D010957:Plasmids / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D013045:Species Specificity; D005879:Tourette Syndrome / Q000150:complications / Q000523:psychology; D000099254:Organic Cation Transporter 3
chemical_list: D008156:Luciferases; D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3