An h Per2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome

Abstract

Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are “morning larks” with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization of the FASPS gene near the telomere of chromosome 2q. A strong candidate gene (h Per2 ), a human homolog of the period gene in Drosophila , maps to the same locus. Affected individuals have a serine to glycine mutation within the casein kinase I ɛ (CKI ɛ ) binding region of hPER2, which causes hypophosphorylation by CKI ɛ in vitro. Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period.

Discovering Endophenotypes for Major Depression

“…There is strong evidence for a genetic control of the human circadian clock (Linkowski et al, 1993), and a familial variant of human sleep behavior has been attributed to a mutation in a human clock gene (Toh et al, 2001). The influence of a functional polymorphism within the angiotensin I-converting enzyme (ACE) gene on partial sleep deprivation in patients with MDD is probably mediated by dopaminergic neurotransmission (Baghai et al, 2003).…”

Pharmacological modulators of the circadian clock as potential therapeutic drugs

“…The best documented example is the genetic association of Familial Advanced Sleep Phase Syndrome (FASPS) with a defect (missence mutation) in the core circadian gene -Period2. The mutation results in a single amino acid change in CK1ε binding domain of the hPER2 molecule, which affects the level of its phosphorylation and stability [55]. More recently, a number of epidemiological studies have suggested that people who work in rotating shifts or at night show a higher incidence of carcinogenesis, heart disease, and metabolic syndrome caused by circadian desynchronization [56][57][58].…”

Genetics of Human Sleep Behavioral Phenotypes

“…Conventionally, to obtain high quantity and quality of DNA, the gold standard is to obtain samples through phlebotomy (Toh et al, 2001;Xu et al, 2005). DNA with optimal quality can be extracted by PAXgene Blood DNA Kit (QIAGEN), GeneCatcher gDNA Blood Kit (Invitrogen), or NucleoSpin Blood (MACHEREY-NAGEL).…”

“…Therefore, the closer the disease variant and a genetic marker (microsatellite or SNP) are on the chromosome, the higher the chances that they will cosegregate (linkage) into the next generation (Strachan & Read, 1999). Based on this property, linkage analysis can track the association of genetic markers and phenotypes to deduce the locus (or loci) that harbors the variants associated with FASP or FNSS (Toh et al, 2001). In practice, logarithm of odds (lod) score is calculated by comparing the likelihood of linkage and no linkage, and a lod score higher than 3 is an accepted threshold for linkage.…”

“…Major breakthroughs in our knowledge of the molecular control of sleep timing and homeostasis have come through studies of familial advanced sleep phase (FASP) and familial natural short sleep (FNSS; He et al, 2009;Jones et al, 1999;Toh et al, 2001;Xu et al, 2005Xu et al, , 2007. FASP and FNSS are Mendelian autosomal dominant sleep phenotypes that significantly deviate from the population norm and run within families.…”