These G608G transgenic mice develop progressive large artery arteriosclerosis and vascular smooth muscle cell loss and may have applications in studies of laminopathies such as Hutchinson-Gilford progeria syndrome.
Francis S. Collins, NHGRI/NIH
Mutations in the human LMNA gene cause Hutchinson-Gilford progeria syndrome, a rare autosomal dominant childhood disease that is characterized by features similar to premature aging, including progressive arteriosclerosis. These transgenic mice express the mutant human lamin A protein progerin, which carries a 50 amino acid C terminus region deletion, and results from the 1824C to T, G608G(encoded amino acid for codon 608 remains glycine), mis-sense mutation of the LMNA gene. Histological analysis of large arteries from hemizygous transgenic mice, beginning at 5 months of age, reveals progressive vascular smooth muscle cell loss, broken elastic fibers, thickened adventitia and medial layers, and proteoglycan and collagen accumulation in large arteries. Hemizygous transgenic mice older than 12 months exhibit calcification and severe vascular smooth muscle cell loss and extracellular matrix deposition of the large arteries. Mice hemizygous for the transgene display impaired blood pressure regulation with an abnormal response to the vasodilator, sodium nitroprusside. The progressive cardiovascular disease observed in transgenic mice recapitulates the cardiovascular pathology seen in human patients. The Donating Investigator reports that homozygous females are infertile and that a lower than expected number of homozygotes are born. For the first 4 months after birth, homozygotes exhibit a slower rate of weight gain when compared to hemizygotes. In addition to developing kyphosis, hair loss, tight skin, loss of subcutaneous fat and joint contracture, homozygotes develop a significantly more severe vascular damage with vascular smooth muscle depletion, calcification, and extremely thick adventitia. Homozygotes die at an average of 8 months of age.
The 164.4 kb human BAC RP11-702H12 containing the entire LMNA gene, as well as the UBQLN4, MAPBPIP, and RAB25 genes was modified to insert the G608G HGPS mutation and a FRT site flanked kanamycin selection cassette into exon 11 of the LMNA gene. The kanamycin selection cassette was removed by transient Flp-recombinase expression. The resulting circular BAC transgene, which contains the G608G mutation in exon 11, and 109 extra nucleotides in intron 10 including an FRT site, EcoRI site, and SacI site, was microinjected into C57BL/6 donor eggs. Founder line H was subsequently established. The mice were maintained on the C57BL/6 background. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.
|Expressed Gene||LMNA, lamin A/C, human|
|Site of Expression|
|Allele Name||transgene insertion H, Francis Collins|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Gene Symbol and Name||Tg(LMNA*G608G)HClns, transgene insertion H, Francis Collins|
|Promoter||LMNA, lamin A/C, human|
|Expressed Gene||LMNA, lamin A/C, human|
|Strain of Origin||C57BL/6|
When maintaining a live colony, hemizygous mice may be bred together, to wildtype siblings, or to C57BL/6J inbred mice (Stock No. 000664). The Donating Investigator reports that homozygous females are infertile, a lower than expected number of homozygotes are born and that homozygotes die at an average age of 8 months.
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