Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression

Neuron. 2005 Jan 6;45(1):11-6. doi: 10.1016/j.neuron.2004.12.014.


Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Animals
  • Arginine / genetics
  • Bipolar Disorder / enzymology
  • Bipolar Disorder / genetics
  • Brain / enzymology*
  • Brain / physiopathology
  • DNA Mutational Analysis
  • Depressive Disorder, Major / enzymology
  • Depressive Disorder, Major / genetics*
  • Female
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Histidine / genetics
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics
  • PC12 Cells
  • Polymorphism, Single Nucleotide / genetics*
  • Rats
  • Serotonin / biosynthesis*
  • Tryptophan Hydroxylase / genetics*


  • Serotonin
  • Histidine
  • Arginine
  • TPH2 protein, human
  • Tryptophan Hydroxylase