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 γ-glutamyl carboxylation, a vitamin K-dependent reaction, to serve in anti-mineralization role in the peripheral connective tissue cells. While 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 γ-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 development of targeted molecular therapies for this, currently intractable, disease.

Juxta-articular joint-capsule mineralization in CD73 deficient mice: Similarities to patients withNT5Emutations

“…The prototype for such conditions is PXE, a multisystem mineralization disorder affecting the skin, the eyes, and the cardiovascular system. 21 This disease, caused by a mutations in the ABCC6 gene, characteristically shows late onset and slow progression of the pathological mineralization processes. In contrast, GACI, caused by mutations in the ENNP1 gene, is frequently diagnosed by pre-or perinatal ultrasound and the affected individuals, born with extensive mineralization of arterial blood vessels, die in www.landesbioscience.commost cases from cardiovascular complications during the first year of life.…”

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

“…Along with relatively benign (but stigmatizing) skin lesions, PXE causes progressive loss of vision and cardiovascular complications (2). The severity of these symptoms is highly variable among patients, even within families (3).…”

The Multifaceted Complexity of Genetic Diseases: A Lesson from Pseudoxanthoma Elasticum

“…The metabolic hypothesis considers liver dismetabolism the only responsible for ectopic calcifications, whereas the peripheral cell hypothesis points to the role of mesenchymal cell metabolism on the homeostatic control of connective tissue calcifications in PXE. The liver metabolic hypothesis postulates that the absence of functional MRP6 activity in hepatocytes results in deficiency of circulating factor(s) physiologically required to prevent aberrant mineralization (Jiang & Uitto, 2006;Uitto et al, 2010). In support of this hypothesis are clinical and experimental observations in PXE patients, as well as in the Abcc6 −/− mouse (Klement et al, 2005), that serves as a model for human PXE.…”

“…To explain the putative mechanisms leading to ectopic calcifications from ABCC6 mutations under normal calcium and phosphorus homeostatic conditions, two theories have been reported in the literature (Uitto et al, 2010): "the liver metabolic hypothesis" and "the peripheral cell hypothesis". The metabolic hypothesis considers liver dismetabolism the only responsible for ectopic calcifications, whereas the peripheral cell hypothesis points to the role of mesenchymal cell metabolism on the homeostatic control of connective tissue calcifications in PXE.…”