Novel insights regarding the pathogenesis and treatment of Pseudoxanthoma Elasticum. S. G. Ziegler1,2, C. R. Ferreira3, A. B. Pinkerton4, J. L. Millan4, W. A. Gahl3, H. C. Dietz1,2 1) Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 2) HHMI, Chevy Chase, MD; 3) MGB, NHGRI, NIH, Bethesda, MD; 4) Sanford-Burnham Medical Research Institute, La Jolla, CA.

   Biallelic mutations in ABCC6, an ATP-dependent transporter whose ligand remains unknown, classically cause pseudoxanthoma elasticum (PXE) characterized by adult-onset elastic fiber calcification in the eyes, skin, and vasculature. Patients with ABCC6 mutations can also develop a more severe phenotype with myocardial infarction and stroke by 3 months of age that is indistinguishable from generalized arterial calcification of infancy (GACI). GACI is more commonly caused by biallelic mutations in ENPP1 that encodes an extracellular enzyme that degrades ATP into AMP and pyrophosphate. We reasoned that elucidation of the mechanism for this striking locus heterogeneity might inform the pathogenesis of ABCC6-associated PXE. A cross between Abcc6 knockout (KO) mice and Enpp1-targeted mice revealed strong evidence for genetic interaction; Abcc6 KO mice with one mutated Enpp1 allele showed acceleration and worsening of the calcification phenotype, as assayed by microCT and echocardiogram. In contrast, Abcc6 KO mice with two targeted Enpp1 alleles were indistinguishable from Enpp1 homozygotes, suggesting that Abcc6 acts upstream of Enpp1. The strong expression of Abcc6 in the liver led to the prevailing view that peripheral tissue calcification in PXE reflects failed liver secretion of an inhibitor of calcification that acts predominantly in an endocrine manner. Contrary to this view, we found that fibroblasts from patients with biallelic mutations in either ABCC6 or ENPP1 had increased tissue non-specific alkaline phosphatase activity (TNAP) and showed a strong tendency for induced calcification in vitro that was prevented by a TNAP inhibitor. Breakdown products of ATP closely regulate TNAP activity suggesting that PXE, like GACI, is caused by defects in extracellular ATP metabolism. Our generation and use of conditional Abcc6-targeted mice revealed that liver-specific deletion using an Albumin-Cre driver failed to recapitulate the PXE calcification phenotype that was observed upon constitutive Abcc6 deletion using CMV-Cre. While a similar strategy was used to exclude the independent relevance of endothelial, vascular smooth muscle and marrow-derived cells, and pericytes, additional studies will explore the candidacy of other lineages. Taken together, these data suggest that PXE is caused by a reversible liver-independent and perhaps cell-autonomous mechanism that induces defects in local extracellular ATP metabolism upstream of Enpp1.

You may contact the first author (during and after the meeting) at