These transgenic mice express a T44A mutant form of the human CSNK1D (casein kinase 1, delta) gene that has been associated with symptoms of Familial Advanced Sleep Phase Syndrome (FASPS) and migraine.
Ying-Hui Fu, University of California, San Francisco
Louis Ptacek, University of California, San Francisco
Mutations in the human CSNK1D (casein kinase 1, delta) gene have been associated with symptoms of Familial Advanced Sleep Phase Syndrome (FASPS) and migraines. A T44A (threonine to alanine) amino acid mutation disrupts a phosphorylation site, shifts circadian patterns in subjects manifesting as symptoms of early sleep times and early-morning awakening, and predisposes them to migraine.
Hemizygous transgenic mice express 2-3 copies of a full-length, T44A mutant form of the human gene. Under 12 hour light-12 hour dark (LD) and constant darkness (DD) conditions, wild-type transgenic (see Stock No. 022149) and mutant transgenic mice show similar and robust circadian rhythms of wheel-running activity. Free-running periods are significantly shorter in mutant transgenic animals compared with wild-type controls, however. Mutant transgenic mice have a circadian periodicity of 23.42 hours under constant dark conditions compared to 23.78 hours in wildtype controls. They also take significantly longer to re-entrain to a light-dark regime after two weeks of constant darkness.
Treatment of mutant transgenic mice with nitroglycerin (NTG) evokes peripheral mechanical and thermal hyperalgesia. Mechanical thresholds are significantly lower in the T44A mice than in wildtype controls, in a migraine-like phenotype. Mice are also more sensitive to thermal stimuli than wildtype siblings, with a significantly lower recovery from thermal hyperalgesia. Ninety minutes after NTG treatment (5 mg/kg, i.p.), females, but not males, show a significant reduction in latency to paw withdrawal from a heat source compared to wildtype. Transgenic mutant animals exhibit lower thresholds to induce cortical spreading depression (a wave of ionic disturbance thought to be similar to migraine aura) during which their arteries are abnormally dilated, as seen during migraine in humans.
Human BAC RP11-1376P16 containing the entire CSNK1D gene on a 190-kb genomic insert (Genbank accession number AC129510) was modified to carry a threonine to alanine mutation at amino acid 44 (T44A). An internal ribosome entry site (IRES) followed by an enhanced green fluorescent protein gene (EGFP) was also added to the carboxy terminus, but fluorescence has not been detected in the transgenic mice. The transgenic vector was introduced to C57BL/6 x SJL F1 embryos. Line 827, carrying 2-3 copies of the transgene was backcrossed for more than 10 generations to C57BL/6 by the donating laboratory.
|Expressed Gene||GFP, Green Fluorescent Protein, jellyfish|
|Site of Expression||Brain|
|Allele Name||transgene insertion 827, Ying-Hui Fu|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence, Reporter)|
|Allele Synonym(s)||Tg(CSNK1D*)827Yfu; hCKIdelta-T44A H|
|Gene Symbol and Name||Tg(CSNK1D*,-EGFP)827Yfu, transgene insertion 827, Ying-Hui Fu|
|Gene Synonym(s)||hCKIdelta-T44A H|
|Promoter||CSNK1D, casein kinase 1 delta, human|
|Expressed Gene||GFP, Green Fluorescent Protein, jellyfish|
|Site of Expression||Brain|
|Strain of Origin||(C57BL/6 x SJL)F1|
|Molecular Note||The human BAC clone RP11-1376P16 containing the CSNK1D gene was targeted to generate a threonine-to-alanine alteration at amino acid 44 in the protein (T44A). An IRES-GFP cassette was also inserted after the stop codon of the CSNK1D gene. Six lines were generated with two of the lines, 827 and 859, being high expressers due to insertion of 2 to 3 copies of the transgene. Transgene expression was confirmed by RT-PCR of brain lysates. This is a representative record for the two high expressing lines.|
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