Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loophelix family member e41) as causal in a family of short sleepers, who needed just 6 h sleep per night. We evaluated whether there were other variants of this gene in two well-phenotyped cohorts. Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase. We identified new variants of the BHLHE41 gene in two cohorts who had either acute sleep deprivation (n = 200) or chronic partial sleep deprivation (n = 217). One variant, Y362H, at another location in the same exon occurred in one twin in a dizygotic twin pair and was associated with reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses during sleep deprivation than the homozygous twin. Both twins had almost identical amounts of non rapid eye movement (NREM) sleep. This variant reduced the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro. Another variant in the same exome had no effect on sleep or response to sleep deprivation and no effect on CLOCK/BMAL1 transactivation. Random mutagenesis identified a number of other variants of BHLHE41 that affect its function. There are a number of mutations of BHLHE41. Mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss. Mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation. Thus, clock mechanisms are likely involved in setting sleep length and the magnitude of sleep homeostasis. Pellegrino R, Kavakli IH, Goel N, Cardinale CJ, Dinges DF, Kuna ST, Maislin G, Van Dongen HP, Tufik S, Hogenesch JB, Hakonarson H, Pack AI. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. SLEEP 2014;37(8):1327-1336.

The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients.

Many have assumed that the primary function of sleep is for the brain. We evaluated the molecular consequences of sleep and sleep deprivation outside the brain, in heart and lung. Using microarrays we compared gene expression in tissue from sleeping and sleep deprived mice euthanized at the same diurnal times. In each tissue, nearly two thousand genes demonstrated statistically significant differential expression as a function of sleep/wake behavioral state. To mitigate the influence of an artificial deprivation protocol, we identified a subset of these transcripts as specifically sleep-enhanced or sleep-repressed by requiring that their expression also change over the course of unperturbed sleep. 3% and 6% of the assayed transcripts showed “sleep specific” changes in the lung and heart respectively. Sleep specific transcripts in these tissues demonstrated highly significant overlap and shared temporal dynamics. Markers of cellular stress and the unfolded protein response were reduced during sleep in both tissues. These results mirror previous findings in brain. Sleep-enhanced pathways reflected the unique metabolic functions of each tissue. Transcripts related to carbohydrate and sulfur metabolic processes were enhanced by sleep in the lung, and collectively favor buffering from oxidative stress. DNA repair and protein metabolism annotations were significantly enriched among the sleep-enhanced transcripts in the heart. Our results also suggest that sleep may provide a Zeitgeber, or synchronizing cue, in the lung as a large cluster of transcripts demonstrated systematic changes in inter-animal variability as a function of both sleep duration and circadian time. Our data support the notion that the molecular consequences of sleep/wake behavioral state extend beyond the brain to include peripheral tissues. Sleep state induces a highly overlapping response in both heart and lung. We conclude that sleep enhances organ specific molecular functions and that it has a ubiquitous role in reducing cellular metabolic stress in both brain and peripheral tissues. Finally, our data suggest a novel role for sleep in synchronizing transcription in peripheral tissues.

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E−09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E−23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E−04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

Melatonin may improve sleep in those with delayed sleep phase disorder but has no effect on primary sleep disorder ( 1 x 1 Ferguson, S.A., Rajaratnam, S.M., and Dawson, D. Melatonin agonists and insomnia. Expert Rev Neurother. 2010; 10: 305–318 Crossref | PubMed | Scopus (45) | Google Scholar See all References ) (1) . Melatonin may also improve initial sleep quality in older adults with insomnia ( 2 x 2 Olde Rikkert, M.G. and Rigaud, A.S. Melatonin in elderly patients with insomnia. A systematic review. Z Gerontol Geriatr. 2001; 34: 491–497 Crossref | PubMed | Scopus (89) | Google Scholar See all References ) (2) , but its role as a treatment for insomnia in those with Alzheimer disease remains disputed ( 3 x 3 Cardinali, D.P., Brusco, L.I., Liberczuk, C., and Furio, A.M. The use of melatonin in Alzheimer's disease. Neuro Endocrinol Lett. 2002; 23: 20–23 PubMed | Google Scholar See all References , 4 x 4 Singer, C., Tractenberg, R.E., Kaye, J., Schafer, K., Gamst, A., Grundman, M. et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep. 2003; 26: 893–901 PubMed | Google Scholar See all References ). Melatonin may also affect immune function as well as cancer initiation and growth ( 5 x 5 Fan, L.L., Sun, G.P., Wei, W., Wang, Z.G., Ge, L., Fu, W.Z. et al. Melatonin and doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines. World J Gastroenterol. 2010; 16: 1473–1481 Crossref | PubMed | Scopus (62) | Google Scholar See all References ) (5) . Melatonin is well tolerated with doses of up to 36 mg/d. However, these high doses may produce some adverse reactions: autoimmune hepatitis, confusion, optic neuropathy, fragmented sleep, psychotic episodes, nistagmus, seizures, headache, and skin eruptions ( 6 x 6 Morera, A.L., Henry, M., and de La Varga, M. Safety in melatonin use. Actas Esp Psiquiatr. 2001; 29: 334–337 PubMed | Google Scholar See all References ) (6) .

Although the specific functions of sleep have not been completely elucidated, the literature has suggested that sleep is essential for proper homeostasis. Sleep loss is associated with changes in behavioral, neurochemical, cellular, and metabolic function as well as impaired immune response. Using high-resolution microarrays we evaluated the gene expression profiles of healthy male volunteers who underwent 60 h of prolonged wakefulness (PW) followed by 12 h of sleep recovery (SR). Peripheral whole blood was collected at 8 am in the morning before the initiation of PW (Baseline), after the second night of PW, and one night after SR. We identified over 500 genes that were differentially expressed. Notably, these genes were related to DNA damage and repair and stress response, as well as diverse immune system responses, such as natural killer pathways including killer cell lectin-like receptors family, as well as granzymes and T-cell receptors, which play important roles in host defense. These results support the idea that sleep loss can lead to alterations in molecular processes that result in perturbation of cellular immunity, induction of inflammatory responses, and homeostatic imbalance. Moreover, expression of multiple genes was downregulated following PW and upregulated after SR compared with PW, suggesting an attempt of the body to re-establish internal homeostasis. In silico validation of alterations in the expression of CETN3, DNAJC, and CEACAM genes confirmed previous findings related to the molecular effects of sleep deprivation. Thus, the present findings confirm that the effects of sleep loss are not restricted to the brain and can occur intensely in peripheral tissues.