Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.TIMELESS | human genetics | mammalian circadian clock regulation | familial advanced sleep phase T he circadian clock governs the timing of many body functions (1), including the onset and offset of sleep, that oscillate with a ∼24-h period (2-5). The mammalian core clock is composed of the positive transcription activators, BMAL1 and CLOCK, and the key negative regulators, PERs and CRYs (3-5). In recent years, studies of human circadian phenotypes have contributed significantly to a better understanding of the molecular clock. Familial advanced sleep phase (FASP) is an inherited condition where affected subjects wake and sleep early (6). We previously showed mutations in the genes (PER2, CRY2, PER3) for negative regulators of the clock that cause the FASP phenotype (7-9). A common feature of these identified mutations is the instability of PER and CRY, causing derepression of BMAL1/CLOCK. This leads to a shortened circadian period and advanced sleep phase. While we have demonstrated that the shortened period is sufficient to cause FASP (7, 8), a mutation that alters entrainment could potentially produce the FASP phenotype with preserved period (10).Although studies have shown the importance of key conserved components of the circadian clock across species (4), much remains unknown of the role for mammalian homologs of Drosophila Timeless (Tim). Tim is a core component of the Drosophila (d) clock, and it functions as the light-sensitive partner of dPer to provide the negative regulation necessary for generating rhythmicity and photoentrainment in flies (11)(12)(13). Based on phylogenetic analysis, mammalian [both mouse (m) and human (h)] Tim has higher sequence homology to Drosophila Timeless2 (Tim2), which was shown to participate in DNA metabolism, maintenance of chromosomal integrity, and light entrainment of the adult clock (14). Homozygosity for mTim knockout is embryonic lethal (at the preimplantation stage), and analysis of viable heterozygous mTim mutant mice showed no change in circadian period (15). Previous studies have shown that mTim levels in the suprachiasmatic nucleus (SCN) oscillate over circadian time with a peak of expression at the day-night transition, similar to that of mPer2 (16). Conditional knockdown of Tim disrupted the rhythmic neuronal firing in ex vivo rat SCN ...
Aims Sleep disturbance is an important factor in the pathophysiology and progression of psychiatric disorders, but whether it is a cause, or a downstream effect is still not clear. Methods To investigate causal relationships between three sleep-associated traits and seven psychiatric diseases, we used genetic variants related to insomnia, chronotype and sleep duration to perform a two-sample bidirectional Mendelian randomisation analysis. Summary-level data on psychiatric disorders were extracted from the Psychiatric Genomics Consortium. Effect estimates were obtained by using the inverse-variance-weighted (IVW), weights modified IVW, weighted-median methods, MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO) test and Robust Adjusted Profile Score (RAPS). Results The causal odds ratio (OR) estimate of genetically determined insomnia was 1.33 (95% confidence interval (CI) 1.22–1.45; p = 5.03 × 10−11) for attention-deficit/hyperactivity disorder (ADHD), 1.31 (95% CI 1.25–1.37; p = 6.88 × 10−31) for major depressive disorder (MDD) and 1.32 (95% CI 1.23–1.40; p = 1.42 × 10−16) for post-traumatic stress disorder (PTSD). There were suggestive inverse associations of morningness chronotype with risk of MDD and schizophrenia (SCZ). Genetically predicted sleep duration was also nominally associated with the risk of bipolar disorder (BD). Conversely, PTSD and MDD were associated with an increased risk of insomnia (OR = 1.06, 95% CI 1.03–1.10, p = 7.85 × 10−4 for PTSD; OR = 1.37, 95% CI 1.14–1.64; p = 0.001 for MDD). A suggestive inverse association of ADHD and MDD with sleep duration was also observed. Conclusions Our findings provide evidence of potential causal relationships between sleep disturbance and psychiatric disorders. This suggests that abnormal sleep patterns may serve as markers for psychiatric disorders and offer opportunities for prevention and management in psychiatric disorders.
Men enrolled in support groups have unique sociodemographic characteristics. Their health related quality of life appears to be better than that of other men with prostate cancer. Whether this is related to support group participation is not known. Additional studies are required to determine whether routine support group participation improves outcomes in men with prostate cancer.
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