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, and apparently acts as a potent dominant negative, disrupting the structure of the nuclear lamina. Once having identified the genetic basis for this disease, we have turned our attention to generating a mouse model. A number of different transgenes for wildtype or mutant lamin A have been constructed and injected into mouse oocytes. Liveborn animals have been obtained, and detailed analysis of their phenotypes is just beginning. We are also tagging the wildtype and mutant protein at the amino-terminal end, in order to follow its fate in the nucleus of transfected cells. We also 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.