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. 2017 Apr 25;7(4):e1106.
doi: 10.1038/tp.2017.75.

Evaluation of Circadian Phenotypes Utilizing Fibroblasts From Patients With Circadian Rhythm Sleep Disorders

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Free PMC article

Evaluation of Circadian Phenotypes Utilizing Fibroblasts From Patients With Circadian Rhythm Sleep Disorders

A Hida et al. Transl Psychiatry. .
Free PMC article

Abstract

We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representative detrended data of Bmal1-luc rhythm (in vitro rhythm) in cultured fibroblasts from a control subject. (a) A linear regression line (dotted line) was calculated using acrophase times for the second cycle (A2), third cycle (A3) and fourth cycle (A4) of the in vitro rhythm. (b) The period length of the Bmal1-luc rhythm (in vitro period) was determined from the slope of the regression line.
Figure 2
Figure 2
The period length of Bmal1-luc rhythm (in vitro period) in the control, DSWPD and N24SWD groups. (a) In vitro periods in 50 control fibroblast samples (open circle), 41 DSWPD fibroblast samples (blue circle) and 26 N24SWD fibroblast samples (red circle). Triangles represent mean in vitro periods in the control group (open), DSWPD group (blue) and N24SWD group (red). Data are presented as mean±s.d.; *P<0.05; **P<0.01. (b) Frequency distribution of in vitro period in control fibroblast samples (open bar), DSWPD fibroblast samples (blue bar) and N24SWD fibroblast samples (red bar). Each bin represents a 0.5 h period. DSWPD, delayed sleep–wake phase disorder; N24SWD, non-24-hour sleep–wake rhythm disorder.
Figure 3
Figure 3
The period length of Bmal1-luc rhythm (in vitro period) in the responders (circle) and non-responders (cross) from the DSWPD (blue) and N24SWD (red) groups. No significant difference was observed in the in vitro period between the responders (R) and non-responders (NR) in the DSWPD group. Longer in vitro period was observed in the non-responders (NR) compared with the responders (R) in the N24SWD group. *One-tailed P<0.05. DSWPD, delayed sleep–wake phase disorder; N24SWD, non-24-hour sleep–wake rhythm disorder.

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