Menstrual cycle-dependent febrile episode mediated by sequence-specific repression of poly(ADP-ribose) polymerase-1 on the transcription of the human serotonin receptor 1A gene

Abstract

The serotonin receptor 1A (encoded by the HTR1A gene) plays a critical role in serotonergic transmission and was linked with many human diseases. A 33-year-old woman with rare menstrual cycle-dependent fever showed abnormal estrogen profile and responded well to the HTR1A agonist buspirone, suggesting that her fevers were allied to estrogen-related HTR1A deficiency. We identified an adenine deletion 480-bases upstream of the translation start site (i.e., -480delA) of HTR1A in this patient. To determine the underlying mechanism of -480delA-mediated HTR1A deficiency, we first showed that HTR1A -480 region can be bound by multiple nuclear protein(s). We then identified poly(ADP-ribose) polymerase (PARP1) as one of the proteins that binds to HTR1A -480 region. Using PARP1 overexpression and knockdown, our data demonstrated that PARP1 represses HTR1A transcription. Furthermore, HTR1A -480delA promoter possesses increased interaction with PARP1 and caused an additional reduction in transcription. Finally, 17β-estradiol administration further reduced transcription associated with the mutant promoter. Altogether, these data suggest that estrogen-induced hyperactivity of HTR1A mutant promoter causes the reduction of HTR1A mRNA and leads to the disruption of HTR1A-mediate hypothermic regulation. This is the first report of HTR1A mutation underlying menstrual cycle-dependent febrile episodes, and implies that similar "febrile episode" cases may also result from the dysfunction of serotonin transmission.

Influence of TPH2 and HTR1A polymorphisms on lifelong premature ejaculation risk among the chinese Han population

“…The main function of HTR1A is to regulate the release of serotonin and the metabolism of dopamine and serotonin. It has been reported that HTR1A affects the occurrence of several diseases including periodic fever, menstrual cycle-dependence febrile episode [ 37 ], generalized anxiety disorder [ 38 ], and schizophrenia [ 39 ]. Previous studies have suggested that HTR1A polymorphisms are associated with various mental diseases, such as major depressive disorder [ 40 ], obsessive-compulsive disorder [ 41 ], and anxiety disorder [ 42 ].…”

Japanese GWAS identifies variants for bust-size, dysmenorrhea, and menstrual fever that are eQTLs for relevant protein-coding or long non-coding RNAs

“…A slight increase in body temperature (0.3–0.5 degrees C) can occur from day 15 to day 25 of a normal 28-day menstrual cycle, but for some women, a greater temperature increase can occur, although it is generally not considered to be pathologic in nature 73 . Over seventy years ago, Reimann termed this “habitual hyperthermia“ 74 , and since then, there have been limited case study reports for some extreme instances of menstrual cycle-dependent febrile episodes 75 – 78 , but to our knowledge, there is no epidemiological report about its frequency and clinical significance. In the current study, the frequencies of subjects reporting QOL impact by menstrual fever was 1.95% (112/5734, LL01) and 2.80% (157/5614, LL02) in the two study stages.…”

Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

“…An interesting case of a 15-bp deletion in the regulatory region of GPR56 (ADGRG1) led to local disruption of GPR56 expression, resulting in restricted polymicrogyria limited to the cortex surrounding the Sylvian fissure (Bae et al, 2014). Menstrual cycle-dependent febrile episodes seem to be caused by a serotonin receptor HTR1A promoter mutation altering receptor expression levels (Jiang et al, 2012).…”