The multifaceted complexity of genetic diseases: a lesson from pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by mineralization of elastic fibers within all connective tissue, although the most important clinical manifestation affect skin, eyes and the cardiovascular system. Despite the dramatic involvement of the extracellular matrix, the first attempts made by researchers to find out the gene defect among those coding for matrix molecules failed and in 2000 three groups, independently, demonstrated that PXE is due to mutation in the ABCC6 gene belonging to the ABC family of membrane transporters. Today the physiological substrate of this transporter is not know and still elusive are the pathogenetic mechanisms linking a defective cellular transporter mainly expressed in liver and kidney to ectopic calcification of connective tissues. This disease may therefore represent a very interesting example of the complexity that regulate molecular pathways, on the influence of metabolism on several other organs/systems. Moreover, there are also evidence that similar endpoints (i.e. clinical and histological alterations) can be observed in some patients starting from different gene defects (Pseudoxanthoma, Beta-thalassemia, vitamin-k dependent coagulation deficiency). These data support the importance of using wide-spread technologies as transcriptomic or proteomic analysis to have a broader view of the cellular pathways that may be involved. Moreover recent findings in the literature highlights the role of polymorphisms in other genes that could be responsible for phenotypic changes and for a different severity of clinical manifestation in this monogenic disorder.