Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic human syndrome of premature aging. Children with this rare condition are normal at birth, but by age 2 they have stopped growing, lost their hair, and shown skin changes and loss of subcutaneous tissue that resemble the ravages of old age. They rarely live past adolescence, dying almost always of advanced cardiovascular disease (heart attack and stroke). The classic syndrome has never been observed to recur in families. Using a genome-wide analysis for homozygosity, we discovered three unique cases of HGPS with either segmental uniparental isodisomy or an interstitial deletion, all involving chromosome 1q. Sequencing a plausible candidate gene in the minimal interval, the gene for lamin A/C (LMNA), we discovered that nearly all cases of HGPS harbor a de novo point mutation in codon 608 of the LMNA gene. Subsequent experiments showed that this mutation causes disease by creating an abnormal splice donor, generating a mRNA with an internal deletion of 150 nt. This is translated into a mutant form of the lamin A protein (referred to now as progerin) that lacks 50 amino acids near the C-terminus. We have shown that progerin acts as a dominant negative to disrupt the structure of the nuclear membrane scaffold. A mouse model for HGPS is being developed. A number of different transgenes for wildtype or mutant lamin A have been constructed and injected into mouse oocytes. Animals carrying a human BAC transgene bearing the codon 608 mutation have generally been infertile, which has complicated the analysis, but pathological examination has shown profound loss of smooth muscle cells in the media of large vessels, with replacement by proteoglycan. These early results provide encouragement that the mouse model will replicate the cardiovascular phenotype of HGPS. We are also exploring the possibility that farnesyl transferase inhibitors might be beneficial in HGPS, since lamin A is a farnesylated protein. Finally, we hypothesize that other structural or regulatory variants in the LMNA gene might actually be protective against the normal aging process. Accordingly, we are developing a detailed catalog of variants in the vicinity of the gene, and testing those in well-matched cohorts of controls and individuals who have achieved exceptional longevity.
