Genetic and biochemical basis of familial advanced sleep phase syndrome in a Utah kindre

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Toh, Kong Leong
Title Genetic and biochemical basis of familial advanced sleep phase syndrome in a Utah kindre
Date 2002-05
Description Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant short-period circadian rhythm variant. The sleep-wake cycles of affected individuals are advanced by 4 hours, a reflection of a reduction in the period (?) of their circadian clocks by approximately 1 hour. This dissertation describes the elucidation of the basis of FASPS in one kindred (K2174), through which it was hoped that novel information on circadian clock regulation could be obtained. In K2174, the FASPS gene was mapped with microsatellite markers to the telomere of the long arm of chromosome 2, where a strong candidate gene, Period2 (hPer2), resides. Sequence analysis of the affected individuals in K2174 identified a missense mutation that alters the serine residue at position 662 of the PERIOD2 protein (hPER2) to glycine. S662G impairs in vitro phosphorylation of hPER2 polypeptides by casein kinase I epsilon (CKI?). As impaired CKI?;-mediated phosphorylation underlies the golden hamster tau mutant, an animal model of FASPS, this observation strongly supports a causative role for S662G. Serine 662 (S662) is the first amino acid of a sequence that forms serial S-X-X-S motifs (where X represents any amino acid) that are CKIϵ substrate recognition sites. Experiments on peptides confirm that S662 phosphorylation initiates the phosphorylation of downstream serines by CKI?;. The number of residues thus modified approaches the predicted value, arguing for the validity of the sequential CKI?-mediated phosphorylation hypothesis. The effects of S662G on the properties of hPER2 in cultured cells were analyzed in an attempt to link impaired phosphorylation at a specific domain of the protein to decreased ?. Preliminary results indicate that S662G may inhibit the nuclear translocation of hPER2 and its ability to regulate the transcription of Bmal1, another circadian clock component.
Type Text
Publisher University of Utah
Subject Utah
Subject MESH Sleep Disorders; Genetics
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "The genetic and biochemical basis of familial advanced sleep phase syndrome in a Utah kindred." Spencer S. Eccles Health Sciences Library.
Rights Management © Kong Leong Toh.
Format Medium application/pdf
Format Extent 6,229,577 bytes
Identifier undthes,3897
Source Original University of Utah Spencer S. Eccles Health Sciences Library (no longer available)
Master File Extent 6,229,603 bytes
ARK ark:/87278/s6jm2cg8
Setname ir_etd
Date Created 2012-04-24
Date Modified 2021-05-06
ID 191485
Reference URL
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