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

Publication ,  Journal Article
Zhang, X; Gainetdinov, RR; Beaulieu, J-M; Sotnikova, TD; Burch, LH; Williams, RB; Schwartz, DA; Krishnan, KRR; Caron, MG
Published in: Neuron
January 6, 2005
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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.

Duke Scholars

Redford B. Williams Jr.
Author Redford B. Williams Jr. Psychiatry & Behavioral Sciences, Behavioral Medicine & Neur ...
K. Ranga Rama Krishnan
Author K. Ranga Rama Krishnan Psychiatry & Behavioral Sciences, Behavioral Medicine & Neur ...
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Published In

Neuron

DOI

10.1016/j.neuron.2004.12.014

ISSN

0896-6273

Publication Date

January 6, 2005

Volume

45

Issue

1

Start / End Page

11 / 16

Location

United States

Related Subject Headings

  • Tryptophan Hydroxylase
  • Serotonin
  • Rats
  • Polymorphism, Single Nucleotide
  • PC12 Cells
  • Neurology & Neurosurgery
  • Mutation
  • Molecular Sequence Data
  • Middle Aged
  • Mice
 

Citation

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Zhang, X., Gainetdinov, R. R., Beaulieu, J.-M., Sotnikova, T. D., Burch, L. H., Williams, R. B., … Caron, M. G. (2005). Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron, 45(1), 11–16. https://doi.org/10.1016/j.neuron.2004.12.014
Zhang, Xiaodong, Raul R. Gainetdinov, Jean-Martin Beaulieu, Tatyana D. Sotnikova, Lauranell H. Burch, Redford B. Williams, David A. Schwartz, K Ranga R. Krishnan, and Marc G. Caron. “Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression.” Neuron 45, no. 1 (January 6, 2005): 11–16. https://doi.org/10.1016/j.neuron.2004.12.014.
Zhang X, Gainetdinov RR, Beaulieu J-M, Sotnikova TD, Burch LH, Williams RB, et al. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron. 2005 Jan 6;45(1):11–6.
Zhang, Xiaodong, et al. “Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression.” Neuron, vol. 45, no. 1, Jan. 2005, pp. 11–16. Pubmed, doi:10.1016/j.neuron.2004.12.014.
Zhang X, Gainetdinov RR, Beaulieu J-M, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KRR, Caron MG. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron. 2005 Jan 6;45(1):11–16.
Journal cover image

Published In

Neuron

DOI

10.1016/j.neuron.2004.12.014

ISSN

0896-6273

Publication Date

January 6, 2005

Volume

45

Issue

1

Start / End Page

11 / 16

Location

United States

Related Subject Headings

  • Tryptophan Hydroxylase
  • Serotonin
  • Rats
  • Polymorphism, Single Nucleotide
  • PC12 Cells
  • Neurology & Neurosurgery
  • Mutation
  • Molecular Sequence Data
  • Middle Aged
  • Mice