title: 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.
authors: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Yu-Chen
authors: YC
authors: Jiang
authors: Hung-Ming
authors: HM
authors: Wu
authors: Kai-Hsin
authors: KH
authors: Cheng
authors: H
authors: H
authors: Sunny Sun
mesh_terms: D000328:Adult; D001483:Base Sequence; D002065:Buspirone / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005334:Fever / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008597:Menstrual Cycle / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D004958:Estradiol; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002065:Buspirone