Functional polymorphisms of the brain serotonin synthesizing enzyme tryptophan hydroxylase-2.

Abstract

Many neuropsychiatric disorders are considered to be related to the dysregulation of brain serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the neuronal-specific enzyme that controls brain serotonin synthesis. There is growing genetic evidence for the possible involvement of TPH2 in serotonin-related neuropsychiatric disorders; however, the degree of genetic variation in TPH2 and, in particular, its possible functional consequences remain unknown. In this short review, we will summarize some recent findings with respect to the functional analysis of TPH2.

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Abstract. Many neuropsychiatric disorders are consid-
ered to be related to the dysregulation of brain serotoner-
gic neurotransmission. Tryptophan hydroxylase-2 (TPH2)
is the neuronal-specific enzyme that controls brain sero-
tonin synthesis. There is growing genetic evidence for the
possible involvement of TPH2 in serotonin-related neu-
Cell. Mol. Life Sci. 63 (2006) 6–11
1420-682X/06/010006-6
DOI 10.1007/s00018-005-5417-4
© Birkhäuser Verlag, Basel, 2006
ropsychiatric disorders; however, the degree of genetic
variation in TPH2and, in particular, its possible functional
consequences remain unknown. In this short review, we
will summarize some recent findings with respect to the
functional analysis of TPH2.
Key words. Brain serotonin; tryptophan hydroxylase-2 (TPH2); single nucleotide polymorphism (SNP); congenic
mice; PC12 cells.
Introduction
The neurotransmitter serotonin (5-hydroxytryptamine, 5-
HT) has been implicated in various physiological func-
tions in both peripheral and central nervous systems
(CNS). Many neuropsychiatric disorders, including de-
pression [1–4], schizophrenia [4–6], aggression and sui-
cidal behavior [1, 6], attention-deficit/hyperactivity dis-
order (ADHD) [7–9], obsessive-compulsive disorder [10]
and autism [11] have been suggested to be related to the
dysregulation of brain serotonergic neurotransmission.
Tryptophan hydroxylase (TPH) is the rate-limiting en-
zyme in 5-HT synthesis and belongs to the superfamily of
aromatic amino acid hydroxylase, which also includes ty-
rosine hydroxylase (TH) and phenylalanine hydroxylase
(PAH). TPH, TH and PAH share considerable structural
similarity and require the same co-factor (Fe2+) and co-
substrate (tetrahydrobiopterin, BH4) for function [12].
While TH and PAH are each encoded by a single gene,
there has been evidence suggesting that two genes may
encode TPH[13, 14]. The recent identification of a TPH2
gene [15] has demonstrated that this is indeed the case.
The well-characterized TPH1 was identified 4 decades
ago [16] and has recently been shown to be essentially pe-
ripheral, being expressed predominantly in the pineal
gland and enterochromaffin cells of the gut [15, 17–19].
In contrast to the results of RNase protection assay [15]
and in situ hybridization study [19], Zill et al. [20] re-
cently reported the expression of TPH1 messenger RNA
(mRNA) in several brain regions in post-mortem human
brains. However, further studies may be needed to exam-
ine whether such TPH1 expression represents the pineal
projections in these brain regions [21], as serotonin N-
acetyltransferase (AANAT), the rate-limiting enzyme in
melatonin synthesis, has been shown to be expressed also
in certain brain regions [21]. TPH2, however, is ex-
pressed predominantly in serotonergic neurons of the
raphe nuclei [15, 19] and in the peripheral myenteric neu-
rons in the gut [18]. To date, TPH2 has been identified
and cloned in human, mice, rat, chicken, zebrafish, tora-
Visions&Reflections
Functional polymorphisms of the brain serotonin
synthesizing enzyme tryptophan hydroxylase-2
X. Zhang, J.-M. Beaulieu, R. R. Gainetdinov and M. G. Caron*
Department of Cell Biology, and Center for Models of Human Disease, Institute for Genome Sciences and Policy,
Box 3287, Duke University Medical Center, Durham, North Carolina 27710 (USA), Fax: +1 919 681 8641,
e-mail: caron002@mc.duke.edu
Received 12 September 2005; received after revision 25 October 2005; accepted 31 October 2005
Online First 27 December 2005
* Corresponding author.
Cellular and Molecular Life Sciences

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fugu and fruit fly (gene accession numbers: NM_173353
[human], NM_173391 [mouse], NM_173839 [rat],
NM_001001301 [chicken], NM_214795 [zebrafish],
AY616189 [torafugu]) [15, 22, 23]. This paper will sum-
marize some recent findings about TPH2, and focus on
the functional analysis of TPH2 and its potential contri-
bution to the dysregulation of brain serotonin homeosta-
sis associated with the pathophysiology of neuropsychi-
atric disorders.
TPH polymorphisms and neuropsychiatric disorders
TPH1 has long been considered the sole rate-limiting en-
zyme for the synthesis of 5-HT. Two common intronic
(non-coding) single nucleotide polymorphisms (SNPs),
A218C and A779C, in TPH1 have been extensively stud-
ied for their possible associations with neuropsychiatric
conditions, including suicidal behavior, unipolar depres-
sion, bipolar depression and schizophrenia with conflict-
ing outcomes (reviewed in [1]). However, the recent dis-
covery of the neuronal-specific TPH2 [15] that is critical
for brain serotonin synthesis [24] has redefined our per-
spective of the serotonergic systems. These findings have
suggested that TPH2, rather than its peripheral counter-
part (TPH1), should be investigated as a candidate gene
for 5-HT-related neuropsychiatric conditions. In fact, a
number of studies have already indicated the possible
association between several TPH2 polymorphisms and
major depression [25–28], suicidal behavior [28, 29],
ADHD [30, 31], autism [32], bipolar disorder [33] and
obsessive-compulsive disorder [34]. In contrast, other
studies have documented in different cohorts a lack of as-
sociation between TPH2 polymorphisms and suicidal be-
havior, schizophrenia, bipolar disorder or depression [35–
37]. Discrepancies in such studies are difficult to recon-
cile, but not unexpected given the different cohorts used
and perhaps the limitations in diagnostic criteria [38]. It is
also noteworthy that most of the SNP in TPH1 and TPH2
identified in the above-mentioned studies are located in
the introns or promoter region, thus corresponding to non-
coding SNPs without clear functional consequences.
These observations underscore the importance of deter-
mining the functional consequences of any given SNP in
order to address whether such SNP(s) would affect TPH2
gene expression (e.g., transcriptional regulation, splicing)
and/or function (e.g., enzyme kinetics, protein folding,
protein stability). As an example of the importance of the
functional consequences of genetic variants, the polymor-
phism in the serotonin transporter (SERT) promoter re-
gion, which is associated with anxiety and depression
[39–41], has been functionally characterized and shown to
result in decreased transcriptional efficiencies.
Serotonin-related neuropsychiatric disorders are complex
heterogeneous disorders with markedly different clinical
profiles and responses to drugs [3, 4], and may also re-
present disorders with different endophenotypes [2]. Ge-
netic, environmental as well as biochemical influences
are thought to represent the contributing factors for these
polygenic disorders which are associated with polymor-
phism(s) in several genes, including the serotonin trans-
porter, serotonin receptors, the vesicular monoamine
transporter, monoamine oxidases, as well as TPH1 and
TPH2 [1–3]. 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 [42]. The multiple functional polymor-
phisms in PAH (see below) and their association with
phenylketonuria (PKU), a metabolic disease with an inci-
dence of 1 per 15,000 in the United States [43] is one ex-
ample supporting the CD/RV hypothesis. Similarly, more
than 100 missense mutations in superoxide dismutase-1
(SOD1) have been identified in amyotrophic lateral scle-
rosis (ALS), a disorder with a frequency of 4–6 per
100,000, yet only 2–3% of ALS patients carry SOD1 mu-
tations [44]. With regard to the TPH2 gene, our labora-
tory has recently identified a G1463A SNP in human
TPH2 resulting in a severe loss-of-function in TPH2,
where a R441H mutation translates to an ~80% decrease
in 5-HT production when assessed in cell culture systems
[27]. The G1463A SNP was identified in a cohort of
unipolar depression subjects who were resistant to vari-
ous forms of pharmacological treatments. Among the 9
subjects carrying the G1463A SNP in a cohort of 87 sub-
jects, 5 subjects were treated with electroconvulsive ther-
apy (ECT), while only 16 subjects in this cohort received
ECT treatment.
TPH2 mutations
To date, over 500 SNPs have been identified in the TPH2
gene among different species, including more than 300
SNPs in human (http://www.ncbi.nlm.nih.gov). Among
these SNPs, there are 6 coding non-synonymous SNPs
(L36P, P206S, A328V , R441H, D479E in humans and
P447R in mice) and 3 coding synonymous SNPs (P312P,
L327L, A375A in humans) [24, 27, 45]. Although the
coding sequence represent only ~1.5% of the TPH2 gene
(93, 600 bp), the prevalence of SNPs (9 to this point) in
coding regions of TPH2 is reminiscent of the genetic
variants in the PAH gene [46, 47]. At present, ~500 muta-
tions, including more than 300 missense mutations, have
been identified in patients with symptoms ranging from
mild hyperphenylalaninemia to severe PKU [46, 47]. Im-
portantly, the amino acids in PAH whose mutations either
cause protein misfolding or affect substrate and/or BH4
Cell. Mol. Life Sci.Vol. 63, 2006
Visions & Reflections
7

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binding [46, 48] are identical in TPH2 (fig. 1). As an ex-
ample, the R441H mutation in TPH2 identified in the
unipolar major depression patients that severely impairs
5-HT production when expressed in cell culture systems
[27] is identical to Arg408 in PAH whose mutation
(R408W) is the most prevalent and severe pathogenic
mutation in PAH [43, 46, 47] Based on the considerable
structural and sequence similarities between TPH2 and
PAH [12], it is likely that additional rare functional muta-
tions 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 complex polygenic
nature and wide range of clinical profiles of 5-HT-related
neuropsychiatric conditions. It is also possible that the
existence of distinct SNPs in TPH2with different degrees
of TPH2dysfunction could contribute to the development
of phenotypes associated with different neuropsychiatric
conditions. Therefore, functional PAH mutations could
provide an important roadmap for understanding the po-
tential mechanisms of TPH2 dysfunction.
Mutations identified in TPH2 may generate missense
and nonsense mutations (coding mutations), splicing
variants (intronic mutations) or other regulatory variants
to affect gene function. Therefore, in order to develop a
better understanding of the relationships between muta-
tions and functions, it is important to functionally char-
acterize TPH2 mutations and correlate them to 5-HT-re-
lated neuropsychiatric disorders. Clearly, a straightfor-
ward approach is to using TPH2 complementary DNA
(cDNA) to assess 5-HT production of coding non-syn-
onymous SNPs in TPH2, whose potential molecular
mechanisms could be predicted based on previous stud-
ies of loss-of-function mutations in PAH. Non-coding
SNPs of TPH2 (i.e., SNPs in promoter regions, untrans-
lated regions, introns) may potentially regulate TPH2
gene functions by transcriptional regulation and splicing.
It should also be mentioned that, while coding synony-
mous SNPs are typically called ‘silent mutations’, more
and more evidence indicates that some of these ‘silent
mutations’may play an important role in regulating pre-
mRNA splicing as a mechanism of gene regulation [49].
For example, an exon-skipping mutation caused by a
coding synonymous SNP in PAH was characterized from
a previously categorized ‘silent mutation’[50]. Thus, it is
necessary to perform detailed studies of TPH2 gene
function using both cDNA and genomic DNA.
PC12 cells as a model system
for characterizing TPH2
Although expression of recombinant protein in Esche-
richia coli is indispensable and has been widely used to
obtain purified TPH1 [51, 52], TPH2 [53] and PAH [46]
in large quantity for further detailed structural and func-
tional analysis, mammalian cell culture systems can pro-
vide conditions for protein expression which are closer
to the in vivo environment. We have established the
pheochromocytoma PC12 cells as a model system to
study 5-HT production [24, 27]. PC12 cells are neuroen-
docrine cells that endogenously synthesize dopamine
and norepinephrine, but not 5-HT [54], indicating that
PC12 cells possess essential elements (e.g., BH4 and
aromatic amino acid decarboxylase [AADC]) for 5-HT
synthesis and are capable of synthesizing 5-HT when
TPH2 is exogenously expressed. Moreover, the presence
of endogenous dopamine in PC12 cells, which is easily
detectable along with 5-HT, provides an ideal internal
control for quantification. Walther et al. [15] have previ-
ously expressed TPH2 in COS7 cells, which do not ex-
press AADC, and measured 5-HTP production as an ap-
proach to effectively monitor the rate of TPH2 synthesis.
Regulation in 5-HT production (e.g., phosphorylation
[53]) and interaction between TPH2 and accessory pro-
teins (e.g., 14-3-3 protein [53]) can also be investigated
in mammalian cell culture systems. TPH2, as well as
other members of the superfamily of aromatic amino
acid hydroxylases, forms homotetramers [12]. Previous
studies using recombinant TPH1 [51] and PAH [47] re-
vealed a tendency of the purified proteins to form aber-
rant oligomers and aggregates, a phenomenon which
may or may not occur in vivo. Therefore, expression of
TPH2 in mammalian cell systems can provide a rapid
functional analysis mimicking the in vivo condition to
identify potential mutation(s) that affect protein folding
and stability in vivo.
8X. Zhang et al. Functional analysis of TPH2
Figure 1. Sequence alignment of TPH2 and PAH in human. Coding
synonymous and coding non-synonymous mutations in human TPH2
are shown with arrows. The coding non-synonymous mutation in
mouse Tph2 is shown with an arrowhead. PAH mutations that affect
substrate binding, protein folding and BH4 binding are indicated with
filled boxes, closed circles and open circles, respectively (gene ac-
cession numbers: NM_173353 [TPH2], NM_000277 [PAH]).

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Animal models for studying 5-HT-related behaviors
It has been noted for many years that there are substantial
behavioral differences among different inbred mouse
strains, particularly in behavioral assessments using the
tail suspension test, forced swim test, alcohol preference
and aggression [55–58]. However, the underlying mecha-
nism governing these differences has been unknown. We
recently identified a functional (C1473G) SNP in mouse
Tph2 that exhibited an ~55% reduction in Tph2 activity
when expressed in PC12 cells [24]. Importantly, BALB/cJ
and DBA/2 inbred mice carrying the homozygous 1473G
allele exhibited an ~50% decrease in the rate of brain 5-
HT synthesis and tissue content as compared with C57Bl/
6 and 129X1/SvJ inbred mice carrying the homozygous
1473C allele [24]. These results provide potential mo-
lecular and genetic explanations for the behavioral dif-
ferences among these strains of mice. Interestingly,
(C1473G) functional polymorphism in mouse Tph2 gene
was recently associated with differences in aggressive be-
havior [59], pre-mRNA editing of the 5-HT2C receptor
[60] and responsiveness to selective serotonin reuptake in-
hibitor (SSRI) [61, 62], but not to certain aspects of im-
pulsive behaviors [63]. These studies have independently
confirmed the homozygous 1473C allele in C57Bl/6,
129X1/SvJ strains and the homozygous 1473G allele in
BALB/cJ, DBA/2 strains. In addition, it has been shown
that other inbred strains carry either the homozygous
1473C allele (ARK/J, C3H/HeJ, CBA/Lac, DD/He, PT/Y,
YT/Y) or the homozygous 1473G allele (A/He, A/J, CBA/
Ca, CC57BR/Mv) [59, 62, 63]. It should be emphasized
that the behavioral studies mentioned above have used
these different inbred mouse strains for comparison; thus
the influence of potential variations in other genes cannot
be ruled out. Therefore, to precisely address the role of
functional polymorphism(s) in behavioral studies, it is im-
perative to generate congenic mice carrying either the
1473C or 1473G allele using a backcross breeding strat-
egy (fig. 2). Congenic mice carrying 1473C/C, 1473C/G
or 1473G/G alleles will enable assessment of the role of
brain 5-HT while minimizing the potential contribution of
other modifier genes. An alternative strategy would be to
generate Tph2 knock-out mice or knock-in mice carrying
functional mutations of TPH2. Such transgenic mice,
along with the congenic mice described above, may reca-
pitulate behavioral manifestations of 5-HT-related neu-
ropsychiatric conditions and provide valuable tools to test
therapeutic pharmacological interventions.
Summary
Brain 5-HT plays an important role in regulating complex
behaviors, and dysregulation of brain 5-HT homeostasis
may contribute to many neuropsychiatric disorders. The
identification of the role of TPH2 in brain 5-HT synthe-
sis has opened a new area to explore the molecular and
genetic mechanisms of 5-HT-related conditions. Func-
tional and genetic analyses are two powerful, indispens-
able and complementary tools to address the role of
TPH2. These studies should also pave the way for the de-
velopment of animal models for behavioral and pharma-
cological studies. Therefore, characterization of TPH2
and its functional SNPs may ultimately provide important
insights into the pathophysiology of 5-HT-related neu-
ropsychiatric disorders.
Acknowledgements. This work was supported by grants from the
National Institutes of Health (MH-40159 and NS-19576). M.G.C.
is the recipient of a Distinguished Investigator Award from
NARSAD. J.-M.B is recipients of a Young Investigator Award from
NARSAD and fellowships from the Human Frontier Research Pro-
gram and the Canadian Institutes of Health Research.
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