Loss-of-Function Mutation in Tryptophan Hydroxylase-2 Identified in Unipolar Major Depression
Open accessAbstract
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.
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Zill et al. and Zhang et al. groups reported genetic modifications that could link TPH2 gene to DD susceptibility.
“In this way, both Zill et al. [232] and Zhang et al. [233] groups reported genetic modifications that could link TPH2 gene to DD susceptibility.”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [233]
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- Authors
- Zhang, X., Gainetdinov, R. R., Beaulieu, J.-M., Sotnikova, T. D., Burch, L. H., Williams, R. B., Schwartz, D. A., Krishnan, K. R. R., & Caron, M. G.
- Affiliations
- Duke University (US)
- Corresponding author
- Caron, Marc G.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 45
- Issue
- 1
- Pages
- 11-16
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2036744872
- Cited by
- 473
- References
- 37
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 3 · 2023: 14 · 2022: 14 · 2021: 15 · 2020: 18 · 2019: 20 · 2018: 11 · 2017: 13 · 2016: 11 · 2015: 19 · 2014: 14 · 2013: 22 · 2012: 25
- FWCI
- 17.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3119 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01 HL36587, P01HL036587)
- National Institute of Mental Health (MH60451, K05-MH79482, P50MH060451)
- National Center for Research Resources (M01 RR 30)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- tryptophan hydroxylase 2, unipolar major depression, loss-of-function mutations, single nucleotide polymorphisms, serotonin synthesis, serotonergic neurotransmission, genetic risk factors, bipolar disorder, PC12 cells
- MeSH terms
- Adult, Amino Acid Sequence, Animals, Arginine, Bipolar Disorder, Brain, Major Depressive Disorder, DNA Mutational Analysis, Female, Gene Frequency, Genetic Testing, Histidine, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Serotonin, Tryptophan Hydroxylase, PC12 Cells, Amino Acid Substitution, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Mice, Rats
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