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Response to Correspondence: Loss-of-Function Mutation in Tryptophan Hydroxylase-2 Identified in Unipolar Major Depression

2005; Cell Press; Volume: 48; Issue: 5 Linguagem: Inglês

10.1016/j.neuron.2005.11.021

1097-4199

Xiao-Dong Zhang, Raul R. Gainetdinov, Jean‐Martin Beaulieu, Tatyana D. Sotnikova, Lauranell H. Burch, Redford B. Williams, David A. Schwartz, K. Ranga Krishnan, Marc G. Caron,

Tryptophan and brain disorders

The TPH2 G1463A polymorphism that we recently reported (Zhang et al., 2005Zhang 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. Neuron. 2005; 45: 11-16Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar) has raised interest among several research groups. This G1463A polymorphism was identified in several individuals within a small cohort of patients with unipolar major depression (n = 87). This coding missense mutation (R441H) causes an ∼80% loss of function in the neuronal-specific TPH2, which could have significant physiological consequence on brain serotonin synthesis (Zhang et al., 2004Zhang X. Beaulieu J.M. Sotnikova T.D. Gainetdinov R.R. Caron M.G. Science. 2004; 305: 217Crossref PubMed Scopus (558) Google Scholar). We concluded that such mutation might provide a potential mechanism underlying dysfunction in serotonin neurotransmission but that further genetic studies would be needed to investigate the inheritance and penetrance of this polymorphism in unipolar major depression. Originally, we identified the G1463A polymorphism in an individual by direct sequencing. Subsequently, several more individuals carrying this mutation were identified in a cohort of unipolar major depression by allele-specific ARMS-PCR (Zhang et al., 2005Zhang 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. Neuron. 2005; 45: 11-16Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar). To further validate the presence of the mutation in these individuals, amplification of a 720 bp PCR product (forward: 5′-ATGCCTTATCACCACCTTCC and reverse: 5′-TTAGATCTGAAAAAGAAAAGGGC) was performed. PCR products were purified and genotyped by sequence analysis on both strands. Furthermore, the G1463A polymorphism was subsequently confirmed in one of our samples by Zhou et al., 2005Zhou Z. Peters E.J. Hamilton S.P. McMahon F. Thomas C. McGrath P.J. Rush J. Trivedi M.H. Charney D.S. Roy A. et al.Neuron. 2005; 48 (this issue): 702-703Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar and Glatt et al., 2005Glatt C.E. Carlson E. Taylor T.R. Risch N. Reus V.I. Schaefer C.A. Neuron. 2005; 48 (this issue): 704-705Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar. In the accompanying letters, Van Den Bogaert et al., 2005Van Den Bogaert A. De Zutter S. Heyrman L. Mendlewicz J. Adolfsson R. Van Broeckhoven C. Del-Favero J. Neuron. 2005; 48 (this issue): 704Abstract Full Text Full Text PDF PubMed Google Scholar, Glatt et al., 2005Glatt C.E. Carlson E. Taylor T.R. Risch N. Reus V.I. Schaefer C.A. Neuron. 2005; 48 (this issue): 704-705Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, and Zhou et al., 2005Zhou Z. Peters E.J. Hamilton S.P. McMahon F. Thomas C. McGrath P.J. Rush J. Trivedi M.H. Charney D.S. Roy A. et al.Neuron. 2005; 48 (this issue): 702-703Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar report that they failed to identify this mutation in several other depression cohorts, pointing to the rarity of this mutation compared to its apparent high frequency in our study. The most plausible explanation for this difference is that the unipolar major depression cohort we had access to represents a unique and different cohort of depression patients as compared to the other groups' cohorts. The subjects in our study (n = 87) were 60 years of age or older, and they were recruited from either our inpatient program or through our mood disorder program. Most of the patients were severely ill, and many were refractory to treatment. Interestingly, 5 of the 9 subjects carrying the G1463A polymorphism were treated with electroconvulsive therapy (ECT), while only 16 subjects in this cohort of 87 received ECT. Therefore, the G1463A polymorphism may be present in a subset of unipolar major depression associated with severe symptoms that are resistant to treatment. ECT is relatively rarely used, and the fact that a high proportion of these subjects had ECT raises the possibility that this mutation may reflect a very small subset of very ill, refractory depressed patients. Unipolar major depression is a complex heterogeneous mood disorder with markedly different clinical profiles and responses to drug treatment (Lesch, 2004Lesch K.P. J. Psychiatry Neurosci. 2004; 29: 174-184PubMed Google Scholar; DSM IV), and may also represent disorders with different endophenotypes (Hasler et al., 2004Hasler G. Drevets W.C. Manji H.K. Charney D.S. Neuropsychopharmacology. 2004; 29: 1765-1781Crossref PubMed Scopus (902) Google Scholar). Genetic and environmental as well as biochemical influences are thought to underlie the manifestations of depression (Hasler et al., 2004Hasler G. Drevets W.C. Manji H.K. Charney D.S. Neuropsychopharmacology. 2004; 29: 1765-1781Crossref PubMed Scopus (902) Google Scholar, Lesch, 2004Lesch K.P. J. Psychiatry Neurosci. 2004; 29: 174-184PubMed Google Scholar; DSM IV). Numerous studies have indicated that depression is a polygenic disorder associated with polymorphism(s) in several genes, including the serotonin transporter, serotonin receptors, the vesicular monoamine transporter, and monoamine oxidases, as well as TPH1 and TPH2. Two hypotheses have been suggested to explain the genetic basis of polygenic disorders: the common disease/common variant (CD/CV) hypothesis, where disease susceptibility variants are common in the population, and the common disease/rare variant (CD/RV) hypothesis with large numbers of rare variants at many loci (Wright et al., 2003Wright A. Charlesworth B. Rudan I. Carothers A. Campbell H. Trends Genet. 2003; 19: 97-106Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). To support the CD/RV hypothesis, it is noteworthy that 495 mutations, including 307 missense mutations, have been reported in phenylalanine hydroxylase (PAH), which cause various degrees of phenylketonuria (PKU), a disorder with an incidence of 1 per 15,000 in the US (Pey et al., 2003Pey A.L. Desviat L.R. Gamez A. Ugarte M. Perez B. Hum. Mutat. 2003; 21: 370-378Crossref PubMed Scopus (103) Google Scholar). PAH and TPH2 belong to the same family of enzymes that share considerable structural and sequence similarities. Strikingly, the G1463A polymorphism (R441H) identified in our study corresponds to the most common and severe mutation (R408W) in PKU patients. Another example is the more than 100 missense mutations in superoxide dismutase-1 (SOD1) identified in amyotrophic lateral sclerosis (ALS), a disorder with a frequency of 4–6 per 100,000, yet only 2%–3% of ALS patients carry SOD1 mutations (Bendotti and Carri, 2004Bendotti C. Carri M.T. Trends Mol. Med. 2004; 10: 393-400Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). It is unlikely that the R441H mutation alone will provide the genetic basis for all cases of depression that affects over 20 million people in the US at any given time with a prevalence of 2%–19% within the general populations (Lesch, 2004Lesch K.P. J. Psychiatry Neurosci. 2004; 29: 174-184PubMed Google Scholar; DSM IV). Rather, the R441H mutation in TPH2 may represent a rare mutation that could be important for a subtype of severe depression. In addition to the R441H mutation in human TPH2 that we reported (Zhang et al., 2005Zhang 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. Neuron. 2005; 45: 11-16Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar), other missense mutations in TPH2 (S41Y, R55C, P206S, A328V, and D479E) have been deposited (Accession numbers rs2887147, rs7488262, and rs17110563) or reported by Zhou et al., 2005Zhou Z. Peters E.J. Hamilton S.P. McMahon F. Thomas C. McGrath P.J. Rush J. Trivedi M.H. Charney D.S. Roy A. et al.Neuron. 2005; 48 (this issue): 702-703Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, but have not yet been characterized functionally. Moreover, additional missense mutations in TPH2 have been identified in our laboratory and are currently being characterized (Zhang et al., 2005Zhang 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. Neuron. 2005; 45: 11-16Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar). In inbred mice, a P447R mutation in Tph2 has been identified to translate in an ∼50% decrease in brain serotonin synthesis (Zhang et al., 2004Zhang X. Beaulieu J.M. Sotnikova T.D. Gainetdinov R.R. Caron M.G. Science. 2004; 305: 217Crossref PubMed Scopus (558) Google Scholar). It is likely that additional functional mutations in TPH2 will be identified and that the presence of multiple susceptibility genes and/or multiple mutations in a single gene may contribute to the polygenic nature and wide range of clinical manifestations of depression.