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. Our laboratory discovered that nearly all cases of HGPS harbor a de novo point mutation in codon 608 of the LMNA gene. 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. Recent data has also demonstrated that progerin interferes with proper chromosome segregation during mitosis.? ? A mouse model for HGPS has been developed. Animals carrying a human BAC transgene bearing the codon 608 mutation show progressive loss of smooth muscle cells in the media of large vessels, with replacement by proteoglycan. Thus, the mouse model nicely replicates the cardiovascular phenotype of HGPS. We have also explored the possibility that farnesyl transferase inhibitors (FTIs) might be beneficial in HGPS, since lamin A is a farnesylated protein. Treatment of progeria fibroflasts growing in cell culture demonstrates that FTIs are capable of reversing the dramatic nuclear blebbing that is the hallmark of the disease. Based on this data, we are conducting a trial of FTIs in the progeria mouse model. A clinical trial of FTIs in children with the disease is planned to be initiated shortly. 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 comparing haplotypes in well-matched cohorts of controls and individuals who have achieved exceptional longevity.
