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

The TPH2 G1463A polymorphism that we recently reported (Zhang et al., 2005xZhang, X., Gainetdinov, R.R., Beaulieu, J.-M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R.R., and Caron, M.G. Neuron. 2005; 45: 11–16Abstract | Full Text | Full Text PDF | PubMed | Scopus (286)See all ReferencesZhang et al., 2005) 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., 2004xZhang, X., Beaulieu, J.M., Sotnikova, T.D., Gainetdinov, R.R., and Caron, M.G. Science. 2004; 305: 217Crossref | PubMed | Scopus (385)See all ReferencesZhang et al., 2004). 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., 2005xZhang, X., Gainetdinov, R.R., Beaulieu, J.-M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R.R., and Caron, M.G. Neuron. 2005; 45: 11–16Abstract | Full Text | Full Text PDF | PubMed | Scopus (286)See all ReferencesZhang et al., 2005). 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. (2005)xZhou, 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: 702–703Abstract | Full Text | Full Text PDF | PubMed | Scopus (13)See all ReferencesZhou et al. (2005) and Glatt et al. (2005)xGlatt, C.E., Carlson, E., Taylor, T.R., Risch, N., Reus, V.I., and Schaefer, C.A. Neuron. 2005; 48: 704–705Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesGlatt et al. (2005).In the accompanying letters, Van Den Bogaert et al., 2005xVan Den Bogaert, A., De Zutter, S., Heyrman, L., Mendlewicz, J., Adolfsson, R., Van Broeckhoven, C., and Del-Favero, J. Neuron. 2005; 48: 704Abstract | Full Text | Full Text PDF | PubMedSee all References, Glatt et al., 2005xGlatt, C.E., Carlson, E., Taylor, T.R., Risch, N., Reus, V.I., and Schaefer, C.A. Neuron. 2005; 48: 704–705Abstract | Full Text | Full Text PDF | PubMedSee all References), and Zhou et al. (2005)xZhou, 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: 702–703Abstract | Full Text | Full Text PDF | PubMed | Scopus (13)See all ReferencesZhou et al. (2005) 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, 2004xLesch, K.P. J. Psychiatry Neurosci. 2004; 29: 174–184PubMedSee all ReferencesLesch, 2004; DSM IV), and may also represent disorders with different endophenotypes (Hasler et al., 2004xHasler, G., Drevets, W.C., Manji, H.K., and Charney, D.S. Neuropsychopharmacology. 2004; 29: 1765–1781Crossref | PubMed | Scopus (623)See all ReferencesHasler et al., 2004). Genetic and environmental as well as biochemical influences are thought to underlie the manifestations of depression (Hasler et al., 2004xHasler, G., Drevets, W.C., Manji, H.K., and Charney, D.S. Neuropsychopharmacology. 2004; 29: 1765–1781Crossref | PubMed | Scopus (623)See all References, Lesch, 2004xLesch, K.P. J. Psychiatry Neurosci. 2004; 29: 174–184PubMedSee all References; 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., 2003xWright, A., Charlesworth, B., Rudan, I., Carothers, A., and Campbell, H. Trends Genet. 2003; 19: 97–106Abstract | Full Text | Full Text PDF | PubMed | Scopus (110)See all ReferencesWright et al., 2003). 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., 2003xPey, A.L., Desviat, L.R., Gamez, A., Ugarte, M., and Perez, B. Hum. Mutat. 2003; 21: 370–378Crossref | PubMed | Scopus (72)See all ReferencesPey et al., 2003). 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, 2004xBendotti, C. and Carri, M.T. Trends Mol. Med. 2004; 10: 393–400Abstract | Full Text | Full Text PDF | PubMed | Scopus (129)See all ReferencesBendotti and Carri, 2004). 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, 2004xLesch, K.P. J. Psychiatry Neurosci. 2004; 29: 174–184PubMedSee all ReferencesLesch, 2004; 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., 2005xZhang, X., Gainetdinov, R.R., Beaulieu, J.-M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R.R., and Caron, M.G. Neuron. 2005; 45: 11–16Abstract | Full Text | Full Text PDF | PubMed | Scopus (286)See all ReferencesZhang et al., 2005), 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. (2005)xZhou, 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: 702–703Abstract | Full Text | Full Text PDF | PubMed | Scopus (13)See all ReferencesZhou et al. (2005), 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., 2005xZhang, X., Gainetdinov, R.R., Beaulieu, J.-M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R.R., and Caron, M.G. Neuron. 2005; 45: 11–16Abstract | Full Text | Full Text PDF | PubMed | Scopus (286)See all ReferencesZhang et al., 2005). In inbred mice, a P447R mutation in Tph2 has been identified to translate in an ∼50% decrease in brain serotonin synthesis (Zhang et al., 2004xZhang, X., Beaulieu, J.M., Sotnikova, T.D., Gainetdinov, R.R., and Caron, M.G. Science. 2004; 305: 217Crossref | PubMed | Scopus (385)See all ReferencesZhang et al., 2004). 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.