An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa

Elastin is the protein responsible for the characteristic elasticproperties of many tissues including the skin, lungs and large bloodvessels. Loss-of-function mutations in the elastin gene are known to causethe heart defect supravalvular aortic stenosis (SVAS). We and others haveidentified deletions, nonsense mutations and splice site mutations in SVASpatients that abolish the function of one elastin gene. We have nowidentified an elastin mutation in a patient with a completely differentphenotype, the rare autosomal dominant condition cutis laxa. A frameshiftmutation in exon 32 of the elastin gene is predicted to replace 37 aminoacids at the C-terminus of elastin by a novel sequence of 62 amino acids.mRNA and immunoprecipitation studies show that the mutant allele isexpressed. Electron microscopy of skin sections shows abnormal branchingand fragmentation in the amorphous elastin component, andimmunocytochemistry shows reduced elastin deposition in the elastic fibresand fewer microfibrils in the dermis. These findings suggest that themutant tropoelastin protein is synthesized, secreted and incorporated intothe elastic matrix, where it alters the architecture of elastic fibres.Interference with cross- linking would reduce elastic recoil in affectedtissues and explain the cutis laxa phenotype.