The aim of this proposal is to understand the biological and pathogenetic basis of elastic fiber defects in a heritable disorder of cutaneous, vascular and ocular tissue, pseudoxanthoma elasticum (PXE). PXE is a heritable disease characterized by the accumulation of abnormal elastic fibers in several elastic tissues, particularly the skin, arteries and the elastic Bruch's membrane of the retina. The aberrant deposition of calcified elastic fibers in these tissues is responsible for the development of the clinical symptoms characteristic of PXE and these include inelastic skin lesions, retinal hemorrhage with partial loss of vision and vascular defects such as gastrointestinal bleeding and myocardial infarction. The pattern of inheritance of PXE is complex and both autosomal dominant and recessive forms of the disease have been reported. Over the last few years, several groups of investigators have attempted to identify the gene mutation(s) responsible for PXE but it has only been in the last two years that three separate laboratories, including our own, have located a major locus for this disease on the short arm of chromosome 16. We have now successfully identified a region at 16p13.1 of 820kb that contains 6 candidate genes, at least one of which will contain the mutations responsible for PXE. With this new information, we hope to identify the 'PXE gene', the mutations in this gene in a cohort of PXE patients and determine a possible function for the product of the PXE gene. These goals are focused on elucidating the biology of PXE and using this information to provide a better understanding of the role of elastic fibers in more common elastic tissue diseases, particularly those skin, vascular and eye disorders characterized by tissue calcification such as the many dystrophic calcification disorders of skin, aneurysms, atherosclerosis and age-related macular degeneration.
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|Beck, Konstanze; Dang, Kaohimanu; Boyd, Charles D (2005) The tissue distribution of murine Abcc6 (Mrp6) during embryogenesis indicates that the presence of Abcc6 in elastic tissues is not required for elastic fiber assembly. J Mol Histol 36:167-70|
|Beck, Konstanze; Hayashi, Kimiko; Nishiguchi, Brian et al. (2003) The distribution of Abcc6 in normal mouse tissues suggests multiple functions for this ABC transporter. J Histochem Cytochem 51:887-902|
|Ilias, Attila; Urban, Zsolt; Seidl, Thomas L et al. (2002) Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem 277:16860-7|
|Le Saux, Olivier; Beck, Konstanze; Sachsinger, Christine et al. (2002) Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa. Hum Genet 111:331-8|
|Le Saux, O; Beck, K; Sachsinger, C et al. (2001) A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. Am J Hum Genet 69:749-64|
|Le Saux, O; Urban, Z; Tschuch, C et al. (2000) Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet 25:223-7|