Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 53

results in familial advanced sleep phase (FASP) in humans and shorter period
in a transgenic mouse model. 14 One route that phosphorylation impinges on
protein turnover is to target the substrate for ubiquitylation and degradation
by the 26S proteasome. CK1-mediated phosphorylation of PER leads to
recruitment of Skp1-Cul1-F-box protein ubiquitin ligase and a ubiquitin
ligase adaptor protein, b -transducin repeat protein ( b -TrCP), leading to
ubiquitylation, and degradation of PER. 15-17 Similarly, an F-box protein
FBXL3 regulates the degradation of CRY. 18-20
Genetic variations of these clock genes can contribute to physiological
changes, which ultimately lead, in some cases, to alterations in disease sus-
ceptibility. In this chapter, we bring together findings from studies that
examine the effects of human clock-gene variations on diverse aspects of
behavior and physiology such as sleep, mood, metabolism, and cancer.

2. BMAL1

BMAL1 variants may play a causative role in type 2 diabetes (T2D)
and hypertension. A genetic association study that examined 1304 individ-
uals from 424 families primarily selected for T2D demonstrates that two
BMAL1 haplotypes are associated with T2D and hypertension. 21 Similarly
in rodents, Bmal1 is located within hypertension susceptibility loci and maps
closely to a region that is genetically divergent between normotensive and
spontaneously hypertensive rat. 21 Cell culture experiments revealed that a
polymorphism in Bmal1 promoter significantly affects transcriptional activa-
tion by GATA-4, which is a transcription factor known to be expressed in
the cardiovascular system. 21 Therefore, this polymorphism could potentially
affect Bmal1 expression in tissues that are critical for regulating blood pres-
sure. Moreover, Bmal1 mutant mice show defects in glucose tolerance,
reduced islet size, islet proliferation, and insulin secretion that worsen with
age, consistent with genetic association studies in human. 22 Conditional
knockout mice with Bmal1 deficiency specifically in the pancreas exhibit
diabetes mellitus due to impaired beta-cell function at the latest stage of
stimulus-secretion coupling. 22 Notably, one of the single-nucleotide poly-
morphisms (SNPs) identified in the human haplotype associated with T2D is
also significantly associated with susceptibility to prostate cancer. 23
BMAL1 has been implicated in the pathogenesis of seasonal affective dis-
order (SAD). SNP analysis in 189 patients and 189 matched controls found an
intronic variation in BMAL1 to be associatedwithwinter depression. Based on
in silico studies, this site may affect the binding of transcription factors. 24