title: A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA ; Center for Sleep and Circadian Neurobiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ; Departamento de Psicobiologia, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Pellegrino
authors.affiliation: Departments of Chemical and Biological Eng. and Molecular Biology and Genetics, Koc University, Rumelifeneri Yolu, Sariyer-Istanbul, Turkey.
authors.forename: Ibrahim Halil
authors.initials: IH
authors.lastname: Kavakli
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ; Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Namni
authors.initials: N
authors.lastname: Goel
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cardinale
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ; Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: David F
authors.initials: DF
authors.lastname: Dinges
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ; Division of Sleep Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ; Department of Medicine, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Kuna
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ; Division of Sleep Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Greg
authors.initials: G
authors.lastname: Maislin
authors.affiliation: Sleep and Performance Research Center, Washington State University, Pullman, WA.
authors.forename: Hans P A
authors.initials: HP
authors.lastname: Van Dongen
authors.affiliation: Departamento de Psicobiologia, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Tufik
authors.affiliation: Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA.
authors.forename: John B
authors.initials: JB
authors.lastname: Hogenesch
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ; Division of Sleep Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Pack
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D056926:CLOCK Proteins / Q000378:metabolism; D015331:Cohort Studies; D004569:Electroencephalography; D005260:Female; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012890:Sleep / Q000235:genetics* / Q000502:physiology*; D012892:Sleep Deprivation / Q000235:genetics*; D013997:Time Factors; D014427:Twins / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; C538960:BMAL1 protein, human; C422085:BHLHE41 protein, human; C538943:CLOCK protein, human
keywords: BHLHE41; delta power; genetics; sleep; sleep deprivation; sleep loss
references.citation: Brain Res Bull. 1993;31(1-2):97-113
references.pmid: 8453498
references.citation: J Appl Physiol (1985). 2002 Feb;92(2):852-62
references.pmid: 11796701
references.citation: Sleep. 2013 Jul 1;36(7):981-990
references.pmid: 23814334
references.citation: Sleep Med Rev. 2006 Feb;10(1):49-62
references.pmid: 16376591
references.citation: Ann Intern Med. 2004 Dec 7;141(11):846-50
references.pmid: 15583226
references.citation: J Appl Physiol (1985). 2005 Nov;99(5):2008-19
references.pmid: 16227462
references.citation: Int J Mol Med. 2006 Jun;17(6):1053-6
references.pmid: 16685415
references.citation: J Neurosci. 2000 Jan 15;20(2):617-25
references.pmid: 10632591
references.citation: Diabetes. 2010 Sep;59(9):2126-33
references.pmid: 20585000
references.citation: Neuroscience. 2000;101(3):523-9
references.pmid: 11113301
references.citation: J Neurosci. 2000 Nov 1;20(21):8138-43
references.pmid: 11050136
references.citation: Am J Physiol. 1996 Jan;270(1 Pt 2):R41-53
references.pmid: 8769783
references.citation: Eur J Neurosci. 2009 May;29(9):1820-9
references.pmid: 19473235
references.citation: PLoS Biol. 2008 Apr 29;6(4):e106
references.pmid: 18447584
references.citation: Hum Neurobiol. 1982;1(3):195-204
references.pmid: 7185792
references.citation: Prog Brain Res. 2010;185:105-29
references.pmid: 21075236
references.citation: Psychiatry Res. 1989 May;28(2):193-213
references.pmid: 2748771
references.citation: Eur J Endocrinol. 2008 Dec;159 Suppl 1:S59-66
references.pmid: 18719052
references.citation: Sleep. 2011 May 01;34(5):581-91
references.pmid: 21532951
references.citation: Ann N Y Acad Sci. 2008;1129:287-304
references.pmid: 18591489
references.citation: Genes Cells. 2012 Feb;17(2):109-21
references.pmid: 22244086
references.citation: Annu Rev Genomics Hum Genet. 2004;5:407-41
references.pmid: 15485355
references.citation: Science. 2003 Jul 18;301(5631):379-83
references.pmid: 12843397
references.citation: Science. 2009 Aug 14;325(5942):866-70
references.pmid: 19679812
references.citation: Aviat Space Environ Med. 2004 Mar;75(3 Suppl):A37-43
references.pmid: 15018264
references.citation: J Biol Rhythms. 2012 Dec;27(6):478-89
references.pmid: 23223373
references.citation: Neurology. 2010 Oct 26;75(17):1509-19
references.pmid: 20975052
references.citation: Sleep. 2004 May 1;27(3):423-33
references.pmid: 15164894
references.citation: J Biol Rhythms. 1999 Dec;14(6):557-68
references.pmid: 10643753
references.citation: Best Pract Res Clin Endocrinol Metab. 2010 Oct;24(5):vii-viii
references.pmid: 21112018
references.citation: J Clin Endocrinol Metab. 2003 Jan;88(1):26-30
references.pmid: 12519823
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D1009-13
references.pmid: 23180795
references.citation: J Biol Chem. 2002 Nov 29;277(48):46544-51
references.pmid: 12297495
references.citation: PLoS One. 2011;6(10):e26622
references.pmid: 22039518
references.citation: Acta Astronaut. 2011 Dec 1;69(11-12):949-959
references.pmid: 22025811
references.citation: Sleep. 1991 Dec;14(6):540-5
references.pmid: 1798888
references.citation: Pharmacopsychiatry. 1987 Jan;20(1):23-9
references.pmid: 3823126
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7118-23
references.pmid: 16636276
references.citation: Open Respir Med J. 2011;5:31-43
references.pmid: 21754974
references.citation: J Neurosci. 2008 Jul 9;28(28):7193-201
references.pmid: 18614689
references.citation: Biochem J. 2004 Aug 15;382(Pt 1):43-50
references.pmid: 15147242
references.citation: Nature. 2002 Oct 24;419(6909):841-4
references.pmid: 12397359
references.citation: Ann Intern Med. 2012 Oct 16;157(8):549-57
references.pmid: 23070488
references.citation: Psychiatry Clin Neurosci. 2001 Jun;55(3):305-10
references.pmid: 11422885
references.citation: Sleep. 2012 Sep 01;35(9):1223-33
references.pmid: 22942500
references.citation: BMC Neurosci. 2002 Dec 20;3:20
references.pmid: 12495442
references.citation: Int J Mol Med. 2007 Jun;19(6):925-32
references.pmid: 17487425