The functional human 5-HT1A C(-1019)G promoter polymorphism (rs6295), which prevents the binding of Deaf-1/NUDR leading to dysregulation of the receptor, has been associated with major depression.
This study reveals sex-specific alterations in gene expression of the pre-synaptic 5-HT1D autoreceptors and 5-HT-related transcription factors, NUDR and REST, in DR neurons of women with MDD.
The serotonin 1A receptor (5-HT1A) and its associated transcriptional regulators, five prime repressor element under dual repression (Freud-1) and nuclear-deformed epidermal autoregulatory factor (NUDR/Deaf-1) have been previously found to be the repressors for 5-HT1A in the serotonergic raphe neurons, and are also altered in postmortem brains of individuals with major depressive disorder (MDD) and in rats exposed to chronic restraint stress.
The 5-HT1A receptor gene is repressed by NUDR/DEAF-1 in raphe cells at the C-, but not at the G-allele of the C(-1019)G polymorphism that is associated with major depression and suicide.
The association with major depression, suicide, and panic disorder of a new functional 5-HT1A polymorphism at C(-1019)G that selectively blocks repression of the 5-HT1A autoreceptor by NUDR further suggests a causative role for altered regulation of this receptor in predisposition to mental illness.