NOVEL BHLHE41 VARIANT ASSOCIATED WITH SHORT SLEEP AND RESISTANCE TO SLEEP LOSS
A Novel BHLHE41 Variant is Associated with Short Sleep and Resistance to Sleep Deprivation in Humans
Renata Pellegrino, PhD1,2,3,*; Ibrahim Halil Kavakli, PhD4,*; Namni Goel, PhD2,5; Christopher J. Cardinale, MD, PhD1; David F. Dinges, PhD2,5; Samuel T. Kuna, MD2,6,7; Greg Maislin, MS, MA2,6; Hans P.A. Van Dongen, PhD8; Sergio Tufik, MD, PhD3; John B. Hogenesch, PhD9; Hakon Hakonarson, MD, PhD1; Allan I. Pack, MBChB, PhD2,6
1Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA; 2Center for Sleep and Circadian Neurobiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 3Departamento de Psicobiologia, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil; 4Departments of Chemical and Biological Eng. and Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Sariyer-Istanbul, Turkey; 5Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 6Division of Sleep Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 7Department of Medicine, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA; 8Sleep and Performance Research Center, Washington State University, Pullman, WA; 9Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; *co-first authors
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.