PATHOGENETICS OF RECESSIVE PSEUDOXANTHOMA ELASTICUM

University Of Hawaii At Manoa, Honolulu HI

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Abstract

DESCRIPTION (provided by applicant): The overall goal of this proposal is to define the mode of inheritance of Pseudoxanthoma elasticum (PXE) and the contribution of heterozygote mutant alleles to the development of partial manifestations of this rare elastic tissue disorder. PXE is a heritable disorder with a highly variable phenotype characterized by skin, ocular and vascular abnormalities that arise through the abnormal calcification of elastic fibers in these tissues. We have recently identified several candidate genes for PXE in a locus at 16pl3.1 and established that mutations in one of these genes, encoding an ABC transporter (ABCC6), contained mutations responsible for the PXE phenotype. These ABCC6 mutations were found in patients from families with apparently recessive and dominant modes of inheritance. In a few families, an apparently dominant mode of inheritance has been shown to be actually due to either pseudo-dominant inheritance of mutant ABCC6 alleles or the presence of partial manifestations of PXE in heterozygous carriers. In addition, our results have demonstrated that obligate carriers presented the characteristics lesions of PXE, indicating incomplete penetrance and partial expression of the phenotype. Based upon this data, we hypothesized that PXE is a truly recessive disorder in which a significant percentage of heterozygote carriers present cardiovascular, ocular and dermal manifestations resembling those of PXE. In this proposal, we intend to study the segregation of ABCC6 mutations in several dominant and recessive pedigrees and evaluate the potentialities for premature cardiovascular and ocular abnormalities associated with single mutant ABBC6 alleles in the general population. In this proposal, therefore, we hope to demonstrate that ABCC6 mutations contribute not only to the development of this rare elastic tissue disorder but also to the genetic susceptibility profile of more common vascular and ocular diseases.