Pseudoxanthoma elasticum: Reduced γ-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6−/−)

Pseudoxanthoma elasticum (PXE), a heritable multi-system disorder manifesting with ectopic mineralization of soft connective tissues, is caused by mutations in the ABCC6/MRP6 gene/protein system, but the mechanisms how the ABCC6 mutations lead to aberrant mineralization are currently unknown. In this study, we utilized a transgenic mouse model, Abcc6−/−, to examine the mineralization processes. We focused on matrix gla protein (MGP) which has been shown to be critical, when activated by γ-carboxylation of glutamyl residues, for prevention of unwanted mineralization. The concentration of MGP in the serum of Abcc6−/− mice was significantly reduced when compared to wild-type controls (p < 0.004). More importantly, MGP isolated from the liver of Abcc6−/− mice was largely under-carboxylated and therefore possesses no activity. Finally, examination of the Abcc6−/− mice revealed association of total and under-carboxylated forms of MGP with ectopic mineralization while the γ-carboxylated form was essentially absent. These results suggest that MGP in Abcc6−/− mice is largely in inactive form and is unable to prevent the unwanted mineralization of connective tissues in PXE.