Mutation
in serotonin synthesis enzyme linked to
increased risk of depression
Dysfunction
of central serotonin (5-HT) neurotransmission is
involved in the pathophysiology of depression.
Many studies have suggested associations between
depression and genes that control the central
functions of monoamine oxidases, the 5-HT
transporter, 5-HT receptors, and the
rate-limiting enzyme of 5-HT synthesis,
tryptophan hydroxylase, TPH2. Studies in mice
revealed a link between a TPH2 gene mutation and
a reduction in 5-HT levels. In addition
mutant mice were reported to display different
behaviors and responses to antidepressants.
Similar mutations in human TPH2 which may affect
brain 5-HT homeostasis in depression have been
investigated.
TPH2 sequences from 300 subjects at risk of
psychosocial and behavioral disorders were
screened. A mutation, replacement of arginine
with histidine, resulted in 80% loss of function
in 5-HT production when expressed in cultured
cells. The mutation was sought in a cohort of 87
patients with unipolar depression, 60 patients
with bipolar depression, and 219 control
subjects.
Nine patients with unipolar depression and three
controls carried the mutant allele, whereas no
carriers of the mutant allele were found among
the bipolar disorder patients. Seven of the nine
patients had family histories of mental illness
or drug and alcohol abuse, and six had exhibited
suicidal behavior or made a suicide attempt. One
of the three controls had generalized anxiety
symptoms, and the other two had mild depression
and a family history of mental illness or drug
and alcohol abuse.
These findings suggest that a mutation in human
TPH2 resulting in a deficiency in brain 5-HT
synthesis may contribute to vulnerability to
unipolar major depression. These observations,
however, merit to be confirmed in larger genetic
studies. Zhang
X, Gainetdinov RR, Beaulieu JM, Sotnikova TD,
Burch LH, Williams RB, Schwartz DA, Krishnan KR,
Caron MG. Loss-of-Function Mutation in
Tryptophan Hydroxylase-2 Identified in Unipolar
Major Depression. Neuron 2005, 45: 11-16.