ELASTIN GENE DEFECTS IN PSEUDOXANTHOMA ELASTICUM

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The aim of this proposal is to identify the mutations in the elastin gene that are responsible for the pathogenesis of a heritable disorder of cutaneous, ocular and vascular tissue, pseudoxanthoma elasticum (PXE). PXE is a genetic disease characterized by the accumulation of abnormal, calcified elastic fibers in several elastic tissues, including skin, arteries and the elastic Bruch's membrane of the retina. Aberrant elastic fiber deposition in these tissues is responsible for the development of the clinical symptoms characteristic of PXE. These symptoms include retinal hemorrhage and associated blindness, papula, inelastic skin lesions and cardiovascular abnormalities that include hypertension and intermittent claudication. Several investigators over the last few years have suggested a functional role for defects in elastic fiber proteins int he development of PXE. However, there has been no direct evidence to date suggesting the presence of any gene mutation(s) responsible for this heritable elastic fiber defect. Elastin is the major protein component of elastic fibers. This insoluble and extensively cross-linked protein is assembled from a soluble precursor, tropoelastin, In this application, we have provided the first direct evidence demonstrating the presence of a mutation in the tropoelastin gene that is responsible for a dominant, phenotypically severe form of PXE. We now hope to characterize mutations in the tropoelastin gene in several PXE patients to determine whether mutations in this gene are responsible for particular phenotypic characteristics of this elastic tissue disorder. PXE is a prototypic elastic fiber disease; the phenotype resembles many of the characteristics of more complex disorders of elastic tissue. A detailed understanding of the functional relationship between tropoelastin gene mutations and the PXE phenotype will provide an important basis for understanding the role of structural defects in elastic fibers in disorders ranging from aging to hypertension and aortic aneurysms.