title: Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2.
abstract: BACKGROUND
  Loss of prokineticin 2 (PROK2) signaling in mice disrupts circadian rhythms, but the role of PROK2 signaling in the regulation of circadian rhythms in humans is undetermined.
  
  
  OBJECTIVE
  The aim of the study was to examine the circadian rhythms of humans with a complete loss-of-function PROK2 mutation using an inpatient constant routine (CR) protocol.
  
  
  METHODS
  We conducted a case study in an academic medical center.
  
  
  METHODS
  Two siblings (one male and one female, ages 67 and 62 y, respectively) with isolated GnRH deficiency (IGD) due to a biallelic loss-of-function PROK2 mutation were studied using an inpatient CR protocol. Historical data from inpatient CR protocols conducted in healthy controls (ages 65-81 y) were used for comparison.
  
  
  METHODS
  We measured circadian phase markers (melatonin, cortisol, and core body temperature) and neurobehavioral performance (psychomotor vigilance task [PVT] and subjective alertness scale).
  
  
  RESULTS
  Circadian waveforms of melatonin and cortisol did not differ between the IGD participants with PROK2 mutation and controls. In both IGD participants, neurobehavioral testing with PVT showed disproportionate worsening of PVT lapses and median reaction time in the second half of the CR.
  
  
  CONCLUSIONS
  Humans with loss of PROK2 signaling lack abnormalities in circadian phase markers, indicating intact central circadian pacemaker activity in these patients. These results suggest that PROK2 signaling in humans is not required for central circadian pacemaker function. However, impaired PVT in the PROK2-null participants despite preserved endocrine rhythms suggests that PROK2 may transmit circadian timing information to some neurobehavioral neural networks.
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine (R.B., J.E.H., A.A.D., N.P., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Sleep Medicine (D.A.C., E.B.K., C.A.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Department of Endocrinology-Hospital São João (D.P.), Department of Experimental Biology-Faculty of Medicine (D.P.), and Institute of Molecular Pathology and Immunology at the University of Porto (IPATIMUP) (D.P.), 4200-319 Porto, Portugal.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Balasubramanian
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Cohen
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Klerman
authors.forename: Duarte
authors.initials: D
authors.lastname: Pignatelli
authors.forename: Janet E
authors.initials: JE
authors.lastname: Hall
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Dwyer
authors.forename: Charles A
authors.initials: CA
authors.lastname: Czeisler
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001683:Biological Clocks / Q000235:genetics; D016022:Case-Control Studies; D021081:Chronobiology Disorders / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D018389:Codon, Nonsense; D005260:Female; D005768:Gastrointestinal Hormones / Q000235:genetics*; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics*; D035781:Siblings; D012890:Sleep / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; D007987:Gonadotropin-Releasing Hormone