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.
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Jiang YC, Wu HM, Cheng KH, Sunny Sun H
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.
Hum Mutat. 2012 Jan;33(1):209-17. doi: 10.1002/humu.21622. Epub 2011 Nov 7.
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- 21990073 [ View in PubMed]
- 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, 17beta-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.