Pseudoxanthoma elasticum: molecular genetics and putative pathomechanisms

Abstract

Pseudoxanthoma elasticum (PXE), a prototypic heritable disorder with ectopic mineralization, manifests with characteristic skin findings, ocular involvement and cardiovascular problems, with considerable morbidity and mortality. The classic forms of PXE are due to loss-of-function mutations in the ABCC6 gene, which encodes ABCC6, a transmembrane efflux transporter expressed primarily in the liver. Several lines of evidence suggest that PXE is a primary metabolic disorder, which in the absence of ABCC6 transporter activity, displays reduced plasma anti-mineralization capacity due to reduced fetuin-A and matrix gla-protein (MGP) levels. MGP requires to be activated by gamma-glutamyl carboxylation, a vitamin K-dependent reaction, to serve in an anti-mineralization role in the peripheral connective tissue cells. Although the molecules transported from the hepatocytes to circulation by ABCC6 in vivo remain unidentified, it has been hypothesized that a critical vitamin K derivative, such as reduced vitamin K conjugated with glutathione, is secreted to circulation physiologically, but not in the absence of ABCC6 transporter activity. As a result, activation of MGP by gamma-glutamyl carboxylase is diminished, allowing slow yet progressive mineralization of connective tissues characteristic of PXE. Understanding of the pathomechanistic details of PXE provides a basis for the development of targeted molecular therapies for this currently intractable disease.

Figure 1. Illustration of the proposed “metabolic hypothesis” of PXE

Under physiologic conditions, the ABCC6 protein is expressed in high levels in the liver and serves as an efflux pump on the baso-lateral surface of hepatocytes transporting critical metabolites from the intracellular milieau to the circulation (right side of the panel). In the absence of ABCC6 transporter activity in PXE, reduced concentrations of such substrate molecules, which may serve as physiologic anti-mineralization factors, are found in the circulation, resulting in mineralization of connective tissues in a number of organs, such as the eye, the arterial blood vessels, the kidneys and the skin (middle panel). The presence of mineralization is illustrated by histopathologic examination (Alizarin red stain) of tissues in Abcc6^-/- mice that recapitulate the features of human PXE. (Modified from Jiang and Uitto, 2006, with permission).

Figure 2. The role of vitamin K in activation of gla-proteins

Vitamin K serves as a co-factor of activation of blood coagulation factors and matrix gla-protein (MGP) by γ-glutamyl carboxylase encoded by the GGCX gene. The γ-glutamyl carboxylase activates coagulation factors (Glu→ Gla), the carboxylated forms are secreted into circulation from hepatocytes and are required for normal blood coagulation (lower panel). In peripheral connective tissue cells, such as fibroblasts, similar activation of uncarboxylated MGP (ucMGP) normally takes place resulting in carboxylated matrix gla-protein (cMGP) which is required for prevention of unwanted mineralization of peripheral tissues under normal calcium and phosphate homeostatic conditions (upper panel). It has been postulated that ABCC6 serves as a transporter molecule transporting vitamin K derivatives, such as the reduced form (KH₂) conjugated with glutathione (GSH). In the absence of ABCC6 transporter activity in PXE, the specific vitamin K co-factor concentrations in the serum and in fibroblasts are reduced resulting in deficient activation of MGP and allowing ectopic mineralization in the adjacent connective tissue to take place. (Modified from Li et al., 2009a, with permission).