Pseudoxanthoma elasticum (PXE), a prototype of heritable multi-system disorders, is characterized by pathologic mineralization of connective tissues, with primary clinical manifestations in the skin, eyes and the cardiovascular system. The causative gene was initially identified as ABCC6 which encodes an ABC transporter protein (ABCC6) expressed primarily in the liver and the kidneys. The critical role of ABCC6 in ectopic mineralization has been confirmed by the development of Abcc6-/- knock-out mice which recapitulate the features of connective tissue mineralization characteristic of PXE. Over 200 distinct loss-of-function mutations representative of over 1000 mutant alleles in ABCC6 have been identified by streamlined mutation detection strategies in this autosomal recessive disease. More recently, missense mutations in the GGCX gene, either in compound heterozygous state or digenic with a recurrent ABCC6 nonsense mutation (p.R1141X), have been identified in patients with PXE-like cutaneous findings and vitamin K-dependent coagulation factor deficiency. GGCX encodes a carboxylase which catalyzes γ-glutamyl carboxylation of coagulation factors as well as of matrix gla protein (MGP) which in fully carboxylated form serves as a systemic inhibitor of pathologic mineralization. Collectively, these observations suggest the hypothesis that a consequence of loss-of-function mutations in the ABCC6 gene is the reduced vitamin K-dependent γ-glutamyl carboxylation of MGP, with subsequent connective tissue mineralization. Further progress in understanding the detailed pathomechanisms of PXE should provide novel strategies to counteract, and perhaps cure, this complex heritable disorder at the genome-environment interface.

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.

A characteristic feature of classic PXE, an autosomal recessive disorder caused by mutations in the ABCC6 gene, is aberrant mineralization of connective tissues, particularly the elastic fibers. Here, we report a family with PXE-like cutaneous features in association with multiple coagulation factor deficiency, an autosomal recessive disorder associated with GGCX mutations. The proband and her sister, both with severe skin findings with extensive mineralization, were compound heterozygotes for missense mutations in the GGCX gene, which were shown to result in reduced γ-glutamyl carboxylase activity and in under-carboxylation of matrix gla protein. The proband’s mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (p.V255M) in GGCX and a null mutation (p.R1141X) in the ABCC6 gene, suggesting digenic nature of their skin findings. Thus, reduced γ-glutamyl carboxylase activity in individuals either compound heterozygous for a missense mutation in GGCX or with haploinsufficiency in GGCX in combination with heterozygosity for ABCC6 gene expression results in aberrant mineralization of skin leading to PXE-like phenotype. These findings expand the molecular basis of PXE-like phenotypes, and suggest a role for multiple genetic factors in pathologic tissue mineralization in general.