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Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by ectopic mineralization of connective tissues and shows considerable intra- and inter-familial phenotypic variability. PXE is caused by mutations in the ABCC6 gene, and targeted ablation of Abcc6 in mouse recapitulates PXE. In this study, we examined the hypothesis that the GGCX gene encoding gamma-glutamyl carboxylase may interfere with the mineralization process in Abcc6 ( -/- ) mice. Thus, Abcc6 ( -/- ) and Ggcx (+/-) mice were generated on 129S1;C57 and 129S1;129X1;C57 genetic backgrounds, respectively, and backcrossed with C57BL/6J for five generations. Thus, these strains differ by the 129X1 contribution to the background of the mice. We then generated Abcc6 ( -/- ) ;Ggcx (+/+) and Abcc6 ( -/- ) ;Ggcx (+/-) mice by crossing Abcc6 ( -/- ) and Ggcx (+/-) mice. The degree of mineralization of connective capsule of vibrissae, a biomarker of the mineralization process in PXE, was evaluated by computerized morphometric analysis and quantified colorimetrically by calcium and phosphate levels in tissues. The mineralization of the vibrissae in Abcc6 ( -/- ) mice takes place at approximately 5-6 weeks of age and is significantly enhanced at 3 months of age in comparison to wild-type mice (&gt;10-fold, p &lt; 0.001). However, the onset of mineralization in Abcc6 ( -/- ) ;Ggcx (+/+) mice was delayed until between 3 and 4 months of age, suggesting that the genetic background plays a role in modifying the mineralization process. The mineralization in the Abcc6 ( -/- ) ;Ggcx (+/- ) mice was accelerated in comparison with age-matched Abcc6 ( -/- ) ;Ggcx (+/+) mice, with approximately 3-fold difference at 3, 4, and 9 months of age (p &lt; 0.01). The mineralization process was also accelerated in these mice by a special custom-designed diet with mineral modifications. These findings suggest a role for both the GGCX gene and the genetic background as well as dietary factors in modulating the phenotypic severity of PXE caused by loss-of-function mutations in ABCC6.

The mineralization phenotype in Abcc6 −/− mice is affected by Ggcx gene deficiency and genetic background—a model for pseudoxanthoma elasticum