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In 1999, Louis Ptáček's research group at the University of California, San Francisco reported findings of a human circadian rhythm disorder showing a familial tendency. The disorder was characterized by a lifelong pattern of sleep onset around 7:30 p.m. and offset around 4:30 a.m. Among three lineages, 29 people were identified as affected with this familial advanced sleep-phase disorder (FASPD), and 46 were considered unaffected. The pedigrees demonstrated FASPD to be a highly penetrant, autosomal dominant trait.
Two years after reporting the finding of FASPD, Ptáček's and Fu's groups published results of genetic sequencing analysis on a family with FASPD. They genetically mapped the FASPD locus to chromosome 2q where very little human genome sequence was then available. Thus, they identified and sequenced all the genes in the critical interval. One of these was Period2 (Per2). Sequencing of the hPer2 gene revealed a serine-to-glycine point mutation in the CKI binding domain of the hPER2 protein that resulted in hypophosphorylation of Per2 in vitro.
In 2005, Fu's and Ptáček's labs reported discovery of a different mutation causing FASPD. This time, CKIδ was implicated, demonstrating an A-to-G missense mutation that resulted in a threonine-to-alanine alteration in the protein. The evidence for both of these reported causes of FASPD is strengthened by the absence of said mutations in all tested control subjects and by demonstration of functional consequences of the respective mutations in vitro. Fruit flies and mice engineered to carry the human mutation also demonstrated abnormal circadian phenotypes although the mutant flies had a long circadian period while the mutant mice had a shorter period. The differences between flies and mammals that account for this difference are not known. Most recently, Ptáček and Fu reported additional studies of the human Per2 S662G mutation and generation of mice carrying the human mutation. These mice had a circadian period almost 2 hours shorter than wild-type animals. Genetic dosage studies of CKIδ on the Per2 S662G mutation revealed that CKIδ is having opposite effects on Per2 levels depending on the sites on Per2 that CKIδ is phosphorylating.
- ↑ Jones, Christopher R., Scott S. Campbell, Stephanie E. Zone, et al. (September 1999). Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans. Nature Medicine 5 (9): 1062–1065.
- ↑ 2.0 2.1 Toh, Kong L., Christopher R. Jones, Yan He, et al. (9 February 2001). An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291 (5506): 1040–1043.
- ↑ 3.0 3.1 Xu, Ying, Quasar S. Padiath, Robert E. Shapiro, et al. (31 March 2005). Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature 434 (7033): 640–644.
- ↑ Xu, Ying, Kong L. Toh, Christopher R. Jones, et al. (12 January 2007). Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 128 (1): 59–70.