Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder 
characterized by features reminiscent of marked premature ageing. Here, we 
present evidence of mutations in lamin A (LMNA) as the cause of this disorder. 
The HGPS gene was initially localized to chromosome 1q by observing two cases of 
uniparental isodisomy of 1q-the inheritance of both copies of this material from 
one parent-and one case with a 6-megabase paternal interstitial deletion. 
Sequencing of LMNA, located in this interval and previously implicated in 
several other heritable disorders, revealed that 18 out of 20 classical cases of 
HGPS harboured an identical de novo (that is, newly arisen and not inherited) 
single-base substitution, G608G(GGC > GGT), within exon 11. One additional case 
was identified with a different substitution within the same codon. Both of 
these mutations result in activation of a cryptic splice site within exon 11, 
resulting in production of a protein product that deletes 50 amino acids near 
the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies 
directed against lamin A revealed that many cells show visible abnormalities of 
the nuclear membrane. The discovery of the molecular basis of this disease may 
shed light on the general phenomenon of human ageing.