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

Authors

  • Yu-Chen Jiang,

    1. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
    • These authors contribute equally to the present study.

  • Hung-Ming Wu,

    1. Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
    Search for more papers by this author
    • These authors contribute equally to the present study.

  • Kai-Hsin Cheng,

    1. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • H. Sunny Sun

    Corresponding author
    1. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    • Institute of Molecular Medicine, National Cheng Kung University Medical College, 1 University Road, Tainan 70101, Taiwan.
    Search for more papers by this author

  • Communicated by Daniel W. Norburt

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. Hum Mutat 33:209–217, 2012. © 2011 Wiley Periodicals, Inc.

Ancillary