Journal of Neural Transmission

, Volume 104, Issue 10, pp 1005–1014

The human serotonin transporter gene polymorphism-basic research and clinical implications

  • A. Heils
  • R. Mößner
  • K. P. Lesch
Special Issue: Serotonin — Basic Research and Clinical Implications


Mood, emotion, and cognition are modulated by the serotonergic midbrain raphe system, which seems to be involved in the pathogenesis of psychiatric disorders like those of the affective spectrum.

Since a dysregulation of serotonin transporter expression might be important in the course of those disorders, we isolated and cloned the 5′-regulatory region of the serotonin transporter gene, which is inducible by cAMP-and PKC-dependend signal transduction pathways.

Systematic screening for length variations and functional promoter analyses revealed a genetic polymorphism with allelic variation in transcriptional activity and protein expression. This 5-HTT gene polymorphism comprises a tandemly repeated sequence in the 5′-regulatory promoter region of the serotonin transporter gene.

Recent population association studies demonstrated the 5-HTT gene promoter polymorphism accounting for 4–5% of population variation of anxiety-related behavioral traits.


Serotonin transporter gene polymorphism allelic association genetics 





serotonin transporter


protein kinase C




Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barker EL, Blakely RD (1995) Norepinephrine and serotonin transporters: molecular targets of antidepressant drugs. In: Bloom FE, Kupfer DJ (eds) Psychopharmcology: the fourth generation of progress. Raven Press, New York, pp 321–333Google Scholar
  2. Blakely RD, Berson HE, Fremeau RT, Caron MC, Peek MM, Prince HK, Bradley CC (1991) Cloning and expression of a functional serotonin transporter rat brain. Nature 354: 66–70Google Scholar
  3. Blakely R, De Felice LJ, Hartzell HC (1994) Molecular physiology of norepinephrine and serotonin transporters. J Exp Biol 196: 263–281Google Scholar
  4. Di Bella D, Catalane M, Balling U, Smeraldi E, Lesch KP (1995) Systematic screening for mutations in the coding region of the 5-HTT gene using PCR and DGGE. Psychiatr Genet 5: S100Google Scholar
  5. Ellis PM, Salmond C (1994) Imipramine binding in depression: a meta analysis. Biol Psychiatry 36: 292–299Google Scholar
  6. Faraj BA, Olkowski ZL, Jackson RT (1994) Expression of a high-affinity serotonin transporter in human lymphocytes. Int J Immunopharmacol 16: 561–567Google Scholar
  7. Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, Riederer P, Lesch KP (1995) Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm 102: 247–254Google Scholar
  8. Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66: 2621–2624Google Scholar
  9. Hoffman BJ, Mezey E, Brownstein M (1991) Cloning of a serotonin transporter affested by antidepressants. Science 254: 579–580Google Scholar
  10. Jayanthi LD, Ramamoorthy S, Mahesh VB, Leibach FH, Ganapathy V (1994) Calmodulin-dependent regulation of the catalytic function of the human serotonin transporter in placental choriocarcinoma cells. J Biol Chem 269: 14424–14429Google Scholar
  11. Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P (1994) Organization of the human serotonin transporter gene. J Neural Transm 95: 157–164Google Scholar
  12. Lesch KP, Franzek E, Gross J, Wolozin BL, Riederer P, Murphy DL (1995) Primary structure of the serotonin transporter in unipolar depression and bipolar disorder. Biol Psychiatry 37: 215–223Google Scholar
  13. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274: 1527Google Scholar
  14. Ramamoorthy S, Cool DR, Mahesh VB, Leibach FH, Melikian HE, Blakely RD, Ganapathy V (1993) Regulation of the human serotonin transporter. J Biol Chem 268: 21626–21631Google Scholar
  15. Ramamoorthy S, Ramamoorthy JD, Prasad PD, Bhat GK, Mahesh VB, Leibach FH, Ganapathy V (1995) Regulation of the human serotonin transporter by Interleukin — 1 beta. Biochem Biophys Res Commun 216: 560–567Google Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • A. Heils
    • 1
  • R. Mößner
    • 1
  • K. P. Lesch
    • 1
  1. 1.Department of PsychiatryUniversity of WürzburgFederal Republic of Germany

Personalised recommendations