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VOLUME 33, ISSUE 05

PER3, DIURNAL PHASE AND DELAY SLEEP PHASE SYNDROME
Polymorphism in the PER3 Promoter Associates with Diurnal Preference and Delayed Sleep Phase Disorder

Simon N. Archer, PhD; Jayshan D. Carpen, PhD; Mark Gibson, MSc; Gim Hui Lim, BSc; Jonathan D. Johnston, PhD; Debra J. Skene, PhD; Malcolm von Schantz, PhD

Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK



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Study Objectives: To screen the PER3 promoter for polymorphisms and investigate the phenotypic associations of these polymorphisms with diurnal preference, delayed sleep phase disorder/syndrome (DSPD/DSPS), and their effects on reporter gene expression.
Design: Interspecific comparison was used to define the approximate extent of the PER3 promoter as the region between the transcriptional start site and nucleotide position −874. This region was screened in DNA pools using PCR and direct sequencing, which was also used to screen DNA from individual participants. The different promoter alleles were cloned into a luciferase expression vector and a deletion library created. Promoter activation was measured by chemiluminescence.
Setting: N/A
Patients or Participants: DNA samples were obtained from volunteers with defined diurnal preference (3 x 80, selected from a pool of 1,590), and DSPD patients (n = 23).
Interventions: N/A
Measurements and Results: We verified three single nucleotide polymorphisms (G −320T, C −319A, G −294A), and found a novel variable number tandem repeat (VNTR) polymorphism (−318 1/2 VNTR). The −320T and −319A alleles occurred more frequently in DSPD compared to morning (P = 0.042 for each) or evening types (P = 0.006 and 0.033). The allele combination TA2G was more prevalent in DSPD compared to morning (P = 0.033) or evening types (P = 0.002). Luciferase expression driven by the TA2G combination was greater than for the more common GC2A (P < 0.05) and the rarer TA1G (P < 0.001) combinations. Deletion reporter constructs identified two enhancer regions (−703 to −605, and −283 to −80).
Conclusions: Polymorphisms in the PER3 promoter could affect its expression, leading to potential differences in the observed functions of PER3.
Keywords: Circadian rhythms, clock genes, genetic polymorphisms, sleep disorders

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