Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 61

lengthening of period versus wild type. Under 12 h light:12 h dark
(12L:12D) conditions, the S662G mice show

4 h phase advance of loco-
motor activity rhythms which is almost identical to that of human FASP sub-
jects carrying this mutation. The S662G mutation does not significantly
affect PER2 degradation or nuclear localization, but it affects PER2 tran-
script levels. In the transgenic mice, both h PER2 and the endogenous mouse
Per2 (m Per2 ) mRNA levels peak earlier for S662G and later for S662D rel-
ative to wild type, corresponding to the shorter and longer behavioral
periods, respectively. Moreover, the mRNA levels are lower in S662Gmice
and higher in S662D mice compared to wild type. Because both mutant
h PER2 and the endogenous wild-type m Per2 transcript levels are reduced
in the S662G mice, this argues for reduced transcriptional activity rather
than reduced PER2 mRNA stability as a result of the mutation.
Consistently, association studies have linked PER2 to diurnal preference
as well. The allele frequency of a SNP in the 5 0 -UTR 12 bases upstream of
the translational start codon of PER2 , -111G, is significantly higher in
individuals with extreme morning preference than individuals with extreme
evening preference. 78 Based on computer prediction, this polymorphism
may alter the secondary structure of PER2 mRNA. A missense variant
1244 Gly/Glu is also associated with morningness: carriers of 1244 Gly
show significantly higher morning scores based on composite scale for
morningness. 79 This 1244 Gly/Glu SNP is also part of a haplotype in
PER2 linked to depression vulnerability. 80 In addition, PER2 has been
implicated in sleep regulation. A synonymous SNP in PER2 , 2229 G/A,
correlates with the duration of sleep for nurses on day shift but not night
shift. 61
The PER2 -111G allele is also linked to reduced activity in adolescents in
the key neural component of the reward circuitry (medial frontal cortex). 81
Supporting the idea of a role for PER2 in reward function, m Per2 mutant
mice exhibit hypersensitized response to cocaine and strong cocaine-
induced place preference. 82 Collectively, these results strongly suggest that
PER2 modulates reward.
The PER2 -111G/C SNP correlates with metabolic and eating behavior-
related phenotypes, including abdominal obesity, probability of withdrawing
fromweight-reduction program, extreme snacking, stress with dieting, eating
when bored, and skipping breakfast. 83 Among individuals withmetabolic syn-
dromes and high levels of saturated fatty acid (SFA), -111G carriers have higher
plasma lipid concentrations, 84 suggesting that the -111G/C allele interacts
with plasma SFA to modify lipid levels.