These transgenic mice express the mutant human lamin A protein, progerin. Progerin is a toxic protein with a 50 amino acid deletion near its C-terminus caused by RNA mis-splicing. The truncation in lamin A eliminates the proteolytic cleavage site for ZMPSTE24 (zinc metallopeptidase, STE24). This dominant negative mutation is a C to T substitution at position 1824 in exon 11 (G608G - encoded amino acid for codon 608 remains glycine).
Hemizygous mice exhibit impaired blood pressure regulation with an abnormal response to the vasodilator, sodium nitroprusside. Histological analysis of large arteries, beginning at 5 months of age, reveals progressive vascular smooth muscle cell loss (VSMC), 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. The progressive cardiovascular disease observed in transgenic mice recapitulates the cardiovascular pathology seen in human patients.
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 VSMC loss in aortic vessel walls, calcification, and periadventitial thickening. Homozygotes die at an average of 7-8 months of age as the result of aortic stiffening and impaired cardiovascular functioning. The Donating Investigator reports that homozygous females are infertile and that a lower than expected number of homozygotes are born.
