NEW YORK (Reuters Health) - A functional single-nucleotide polymorphism (SNP) in the tryptophan hydroxylase (TPH)-2 gene is associated with unipolar major depression, according to a report in the December 9th online publication of Neuron.
“We have essentially identified the first functional mutation in a gene that control levels of serotonin in the brain,” Dr. Marc G. Caron from Duke University Medical Center, Durham, North Carolina told Reuters Health. “Our discovery of a functional mutation in TPH2 is actually the first directly tangible piece of evidence that levels of serotonin in the central nervous system may be related to symptoms of depression.”
Prompted by studies in mice, which linked a TPH2 mutation to reduced serotonin levels, Dr. Caron and colleagues screened THP2 sequences from some 300 individuals at risk of psychosocial and behavioral disorders.
One polymorphism in the coding region resulted in the replacement of arginine with histidine (R441H). Pheochromocytoma cells transfected with this mutant form of TPH2 expressed 80% lower levels of serotonin than did cells transfected with wild-type TPH2, the investigators note, “indicating a severe loss of function in the ability of the mutant enzyme to synthesize serotonin.”
Nine unipolar major depression patients out of 87 tested carried the mutant allele, as did 3 of 219 control subjects.
Seven of the 9 patients had been unresponsive to treatment with a selective serotonin reuptake inhibitor (SSRI), the researchers report, whereas the other 2 were responsive only to the highest doses of SSRI.
One of the 3 controls bearing the mutant allele had generalized anxiety symptoms, and the other 2 had mild depression and a family history of mental illness or drug and alcohol abuse.
“Clearly,” the investigators write, “further large-scale genetic studies are needed to confirm these observations and to investigate in detail the inheritance and penetrance of this functional SNP in human TPH2 in unipolar major depression.”
Nevertheless, Dr. Caron concluded, “the relationship between the mutation and the response to SSRI is a most interesting aspect of our study. Such genetic testing might in the future guide physicians in their choice of therapeutic approaches to treat conditions like major unipolar depression.”
Neuron 2004.
MeSH Headings:Polymorphism, Single NucleotideCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
