The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes.
As a result, activation of MGP by gamma-glutamyl carboxylase is diminished, allowing slow yet progressive mineralization of connective tissues characteristic of PXE.
As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome.
Thus, reduced gamma-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.
Our hypothesis explains the known facts of PXE and also explains why PXE-like symptoms can occur in patients with mutations in the gamma-glutamyl carboxylase gene (encoding the enzyme responsible for protein carboxylase) and in rats treated with vitamin K antagonists.
PXE-like phenotypes have been observed in a number of disorders, with no evidence of mutations in ABCC6.Vanakker et al. report PXE-like skin findings in patients with mutations in GGCX critical for gamma-carboxylation of gla-proteins.