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.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Buspirone / administration & dosage
  • Buspirone / therapeutic use
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Estradiol / pharmacology
  • Female
  • Fever / drug therapy
  • Fever / genetics*
  • Fever / metabolism
  • Gene Expression Regulation
  • Humans
  • Menstrual Cycle / physiology*
  • Molecular Sequence Data
  • Mutation*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Promoter Regions, Genetic
  • Receptor, Serotonin, 5-HT1A / genetics*
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Serotonin / metabolism
  • Serotonin Receptor Agonists / administration & dosage
  • Serotonin Receptor Agonists / therapeutic use
  • Transcription, Genetic
  • Transfection


  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Estradiol
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Buspirone