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Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2
Ravikumar Balasubramanian1, Daniel A Cohen, Elizabeth B Klerman
1Harvard 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.
Context:
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.
Design And Setting:
We conducted a case study in an academic medical center.
Subjects And 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.
Main Outcome Measures:
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.
Insights
Prokineticin 2 (PROK2) signaling is not essential for human circadian rhythm phase markers. However, loss of PROK2 function impairs neurobehavioral performance, suggesting a role in transmitting circadian timing information.
Area of Science:
- Neuroscience
- Endocrinology
- Chronobiology
Background:
- Prokineticin 2 (PROK2) signaling is known to disrupt circadian rhythms in mice.
- The role of PROK2 in human circadian rhythm regulation remains unclear.
Purpose of the Study:
- To investigate the circadian rhythms in humans with a complete loss-of-function PROK2 mutation.
- Utilize an inpatient constant routine (CR) protocol to assess circadian markers and neurobehavioral performance.
Main Methods:
- Case study involving two siblings with isolated GnRH deficiency (IGD) due to a PROK2 mutation.
- Inpatient CR protocol measuring melatonin, cortisol, core body temperature, and psychomotor vigilance task (PVT).
- Comparison with historical data from healthy controls.
Main Results:
- Circadian waveforms of melatonin and cortisol were similar between PROK2-mutated individuals and controls.
- Individuals with PROK2 mutation showed disproportionate worsening in PVT lapses and reaction time during the latter half of the CR.
- Endocrine rhythms remained preserved despite neurobehavioral deficits.
Conclusions:
- PROK2 signaling is not required for the central circadian pacemaker function in humans.
- Preserved endocrine rhythms indicate intact central circadian pacemaker activity.
- Impaired PVT suggests PROK2 signaling transmits circadian timing information to specific neurobehavioral networks.
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