Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau.
The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIepsilon), a homolog of the Drosophila circadian gene double-time. In vitro expression and functional studies of wild-type and tau mutant CKIepsilon enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIepsilon can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIepsilon and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.
Lowrey
P L
PL
Department of Neurobiology and Physiology, Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208, USA.
Shimomura
K
K
Antoch
M P
MP
Yamazaki
S
S
Zemenides
P D
PD
Ralph
M R
MR
Menaker
M
M
Takahashi
J S
JS
D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D047388:Casein Kinases; D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D002940:Circadian Rhythm / Q000235:genetics; D003001:Cloning, Molecular; D006224:Cricetinae; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008647:Mesocricetus; D051379:Mice; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010641:Phenotype; D010766:Phosphorylation; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C539022:PER1 protein, human; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011494:Protein Kinases; D047388:Casein Kinases