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Title: A Novel BHLHE41 Variant is Associated with Short Sleep and Resistance to Sleep Deprivation in Humans
Authors: Pellegrino, Renata [UNIFESP]
Kavakli, Ibrahim Halil
Goel, Namni
Cardinale, Christopher J.
Dinges, David F.
Kuna, Samuel T.
Maislin, Greg
Van Dongen, Hans P. A.
Tufik, Sergio [UNIFESP]
Hogenesch, John B.
Hakonarson, Hakon
Pack, Allan I.
Childrens Hosp Philadelphia
Univ Penn
Universidade Federal de São Paulo (UNIFESP)
Koc Univ
Philadelphia Vet Affairs Med Ctr
Washington State Univ
Keywords: BHLHE41
delta power
sleep deprivation
sleep loss
Issue Date: 1-Aug-2014
Publisher: Amer Acad Sleep Medicine
Citation: Sleep. Westchester: Amer Acad Sleep Medicine, v. 37, n. 8, p. 1327-U127, 2014.
Abstract: Study Objectives: Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loop-helix 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.Design: Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase.Results: 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.Conclusions: 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.
ISSN: 0161-8105
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