title: Pseudoxanthoma elasticum: reduced gamma-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6-/-).
abstract: 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 gamma-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 gamma-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.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.forename: Qiujie
authors.initials: Q
authors.lastname: Jiang
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D003238:Connective Tissue / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011561:Pseudoxanthoma Elasticum / Q000378:metabolism* / Q000473:pathology; D000097568:Matrix Gla Protein
chemical_list: D018528:ATP-Binding Cassette Transporters; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000097568:Matrix Gla Protein; C504743:Abcc6 protein, mouse