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  • The International Journal of Neuropsychopharmacology, Volume 11, Issue 1
  • February 2008, pp. 35-48

Novel mutations of the extraneuronal monoamine transporter gene in children and adolescents with obsessive–compulsive disorder

  • Andreas Lazar (a1), Susanne Walitza (a2), Alexander Jetter (a1), Manfred Gerlach (a2), Andreas Warnke (a2), Beate Herpertz-Dahlmann (a3), Dirk Gründemann (a1), Gundula Grimberg (a1), Eberhard Schulz (a4), Helmut Remschmidt (a5), Christoph Wewetzer (a2) and Edgar Schömig (a1)
  • DOI:
  • Published online: 04 May 2007

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.

Corresponding author
Address for correspondence: A. Lazar, M.D., Department of Pharmacology, University Hospital, University of Cologne, Gleueler Str. 24, 50931 Köln, Germany. Tel.: +49-221-478-4196Fax: +49-221-478-5022E-mail:
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AH Abdelmawla , RW Langley , E Szabadi , CM Bradshaw (1999). Comparison of the effects of venlafaxine, desipramine, and paroxetine on noradrenaline- and methoxamine-evoked constriction of the dorsal hand vein. British Journal of Clinical Pharmacology 48, 345354.

U Albert , C Bergesio , E Pessina , G Maina , F Bogetto (2002). Management of treatment resistant obsessive-compulsive disorder. Algorithms for pharmacotherapy. Panminerva Medica 44, 8391.

JP Alsobrook 2nd, AH Zohar , M Leboyer , N Chabane , RP Ebstein , DL Pauls (2002). Association between the COMT locus and obsessive-compulsive disorder in females but not males. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics 114, 116120.

APA (1994). Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (4th edn). Washington DC: American Psychiatric Association.

C Benkelfat , IN Mefford , CF Masters , TE Nordahl , AC King , RM Cohen , DL Murphy (1991). Plasma catecholamines and their metabolites in obsessive-compulsive disorder. Psychiatry Research 37, 321331.

RA King , L Scahill (1995). In: MM Robertson , Eapen (Eds.), Movement and Allied Disorders in Childhood (pp. 4256). New York: John Wiley and Sons.

EA Billett , MA Richter , N King , A Heils , KP Lesch , JL Kennedy (1997). Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Molecular Psychiatry 2, 403406.

F Brambilla , L Bellodi , G Perna , C Arancio , A Bertani , G Perini , C Carraro , F Gava (1997). Noradrenergic receptor sensitivity in obsessive compulsive disorder: II. Cortisol response to acute clonidine administration. Psychiatry Research 69, 163168.

B Camarena , G Rinetti , C Cruz , S Hernandez , JR de la Fuente , H Nicolini (2001). Association study of the serotonin transporter gene polymorphism in obsessive-compulsive disorder. International Journal of Neuropsychopharmacology 4, 269272.

B Dell'Osso , G Nestadt , A Allen , E Hollander (2006). Serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive-compulsive disorder: a critical review. Journal of Clinical Psychiatry 67, 600610.

JT den Dunnen , SE Antonarakis (2001). Nomenclature for the description of human sequence variations. Human Genetics 109, 121124.

D Denys , HJ van Megen , N van der Wee , HG Westenberg (2004). A double-blind switch study of paroxetine and venlafaxine in obsessive-compulsive disorder. Journal of Clinical Psychiatry 65, 3743.

XP Dong , F Stubenrauch , E Beyer-Finkler , H Pfister (1994). Prevalence of deletions of YY1-binding sites in episomal HPV 16 DNA from cervical cancers. International Journal of Cancer 58, 803808.

G Eisenhofer (2001). The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacology and Therapeutics 91, 3562.

MA Enoch , WH Kaye , A Rotondo , BD Greenberg , DL Murphy , D Goldman (1998). 5-HT2A promoter polymorphism -1438G/A, anorexia nervosa, and obsessive-compulsive disorder. Lancet 351, 17851786.

A Frisch , E Michaelovsky , R Rockah , I Amir , H Hermesh , N Laor , C Fuchs , J Zohar , B Lerer , SF Buniak , (2000). Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways. European Neuropsychopharmacology 10, 205209.

DA Geller , J Biederman , SV Faraone , CA Bellordre , GS Kim , L Hagermoser , K Cradock , J Frazier , BJ Coffey (2001). Disentangling chronological age from age of onset in children and adolescents with obsessive–compulsive disorder. International Journal of Neuropsychopharmacology 4, 169178.

DA Geller , J Biederman , SE Stewart , B Mullin , A Martin , T Spencer , SV Faraone (2003). Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder. American Journal of Psychiatry 160, 19191928.

WK Goodman , LH Price , SA Rasmussen , C Mazure , RL Fleischmann , CL Hill , GR Heninger , DS Charney (1989). The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Archives of General Psychiatry 46, 10061011.

D Gordon , SC Heath , X Liu , J Ott (2001). A transmission/disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data. American Journal of Human Genetics 69, 371380.

D Gründemann , AC Koschker , C Haag , C Honold , T Zimmermann , E Schömig (2002). Activation of the extraneuronal monoamine transporter (EMT) from rat expressed in 293 cells. British Journal of Pharmacology 137, 910918.

D Gründemann , B Schechinger , GA Rappold , E Schömig (1998). Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nature Neuroscience 1, 349351.

D Gründemann , E Schömig (2000). Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. Human Genetics 106, 627635.

C Haag , R Berkels , D Gründemann , A Lazar , D Taubert , E Schömig (2004). The localisation of the extraneuronal monoamine transporter (EMT) in rat brain. Journal of Neurochemistry 88, 291297.

I Hand , H Büttner-Westphal (1991). Die Yale-Brown Obsessive Compulsive Scale (YBOCS): Ein halbstrukturiertes Interview zur Beurteilung des Schweregrades von Denk- und Handlungszwängen. Verhaltenstherapie 1, 223225.

D Hall , A Dhilla , A Charalambous , JA Gogos , M Karayiorgou (2003). Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. American Journal of Human Genetics 73, 370376.

J Hebebrand , B Klug , R Fimmers , SA Seuchter , R Wettke-Schafer , F Deget , A Camps , S Lisch , K Hebebrand , A von Gontard , (1997). Rates for tic disorders and obsessive compulsive symptomatology in families of children and adolescents with Gilles de la Tourette syndrome. Journal of Psychiatric Research 31, 519530.

GL Hanna , A Yuwiler , JK Coates (1995). Whole blood serotonin and disruptive behaviors in juvenile obsessive-compulsive disorder. Journal of the American Academy of Child and Adolescent Psychiatry 34, 2835.

E Hollander , A Allen , M Steiner , DE Wheadon , R Oakes , DB Burnham (2003). Acute and long-term treatment and prevention of relapse of obsessive-compulsive disorder with paroxetine. Journal of Clinical Psychiatry 64, 11131121.

T Jans , C Wewetzer , K Klampfl , E Schulz , B Herpertz-Dahlmann , H Remschmidt , A Warnke (2007). Phenomenology and co-morbidity of childhood onset obsessive compulsive disorder [in German]. Zeitschrift für Kinder- und Jugendpsychiatrie 35, 4150.

E Hollander , C DeCaria , A Nitescu , T Cooper , B Stover , R Gully , DF Klein , MR Liebowitz (1991). Noradrenergic function in obsessive-compulsive disorder: behavioral and neuroendocrine responses to clonidine and comparison to healthy controls. Psychiatry Research 37, 161177.

M Karayiorgou , M Altemus , BL Galke , D Goldman , DL Murphy , J Ott , JA Gogos (1997). Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proceedings of the National Academy of Sciences USA 94, 45724575.

M Karayiorgou , C Sobin , ML Blundell , BL Galke , L Malinova , P Goldberg , J Ott , JA Gogos (1999). Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biological Psychiatry 45, 11781189.

A Lazar , D Gründemann , R Berkels , D Taubert , T Zimmermann , E Schömig (2003). Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). Journal of Human Genetics 48, 226230.

CJ McDougle , LC Barr , WK Goodman , LH Price (1999). Possible role of neuropeptides in obsessive compulsive disorder. Psychoneuroendocrinology 24, 124.

B Millet , N Chabane , R Delorme , M Leboyer , S Leroy , MF Poirier , MC Bourdel , MC Mouren-Simeoni , F Rouillon , H Loo , MO Krebs (2003). Association between the dopamine receptor D4 (DRD4) gene and obsessive-compulsive disorder. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics 116, 5559.

R Mossner , S Walitza , F Geller , A Scherag , L Gutknecht , C Jacob , L Bogusch , H Remschmidt , M Simons , B Herpertz-Dahlmann , (2006). Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder. International Journal of Neuropsychopharmacology 9, 437442.

CB Nemeroff , MJ Owens (2004). Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis. CNS Spectrums 9, 2331.

G Nestadt , J Samuels , M Riddle , OJ Bienvenu 3rd, KY Liang , M LaBuda , J Walkup , M Grados , R Hoehn-Saric (2000). A family study of obsessive-compulsive disorder. Archives of General Psychiatry 57, 358363.

DR Rosenberg , CM Stewart , KD Fitzgerald , V Tawile , E Carroll (1999). Paroxetine open-label treatment of pediatric outpatients with obsessive-compulsive disorder. Journal of the American Academy of Child and Adolescent Psychiatry 38, 11801185.

L Scahill , MA Riddle , M McSwiggin-Hardin , SI Ort , RA King , WK Goodman , D Cicchetti , JF Leckman (1997). Children's Yale–Brown Obsessive Compulsive Scale: reliability and validity. Journal of the American Academy of Child and Adolescent Psychiatry 36, 844852.

JJ Schildkraut , JJ Mooney (2004). Toward a rapidly acting antidepressant: the normetanephrine and extraneuronal monoamine transporter (uptake 2) hypothesis. American Journal of Psychiatry 161, 909911.

E Schömig , H Russ , K Staudt , F Martel , M Gliese , D Gründemann (1998). The extraneuronal monoamine transporter exists in human central nervous system glia. Advances in Pharmacology 42, 356359.

YY Shugart , J Samuels , VL Willour , MA Grados , BD Greenberg , JA Knowles , JT McCracken , SL Rauch , DL Murphy , Y Wang , (2006). Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Molecular Psychiatry 11, 763770.

S Unnewehr (1995). Diagnosis of psychiatric disorders in children and adolescents using structured interviews [in German]. Zeitschrift für Kinder- und Jugendpsychiatrie 23, 121132.

S Walitza , C Wewetzer , A Warnke , M Gerlach , F Geller , G Gerber , T Gorg , B Herpertz-Dahlmann , E Schulz , H Remschmidt , (2002). 5-HT2A promoter polymorphism -1438G/A in children and adolescents with obsessive-compulsive disorders. Molecular Psychiatry 7, 10541057.

X Wu , R Kekuda , W Huang , YJ Fei , FH Leibach , J Chen , SJ Conway , V Ganapathy (1998). Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. Journal of Biological Chemistry 273, 3277632786.

JH Zhao , S Lissarrague , L Essioux , PC Sham (2002). GENECOUNTING: haplotype analysis with missing genotypes. Bioinformatics 18, 16941695.

J Zohar , M Chopra , Y Sasson , R Amiaz , D Amital (2000). Obsessive compulsive disorder: serotonin and beyond. World Journal of Biological Psychiatry 1, 92100.

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