부산대학교 도서관

Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported ENPP1 variants suggested pathogenicity. The two PXE patients, currently 57 and 27 years of age, had diagnostic features of PXE and had not manifested the GACI phenotype. The similarly reduced PPi plasma concentrations in the PXE and GACI patients in our study correlate poorly with their disease severity. This study demonstrates that in addition to GACI, ENPP1 variants can cause classic PXE, expanding the clinical and genetic heterogeneity of heritable ectopic calcification disorders. Furthermore, the results challenge the current prevailing concept that plasma PPi governs the severity of ectopic calcification. Author summary: Biallelic inactivating mutations in the ENPP1 gene cause generalized arterial calcification of infancy (GACI), a fatal disease characterized by infantile onset of widespread arterial calcification and/or narrowing of large and medium-sized vessels resulting in the early demise of affected individuals. Significantly reduced, almost zero plasma levels of a potent and endogenous calcification inhibitor–inorganic pyrophosphate (PPi), is the underlying cause of vascular calcification in GACI. Mutations in ENPP1 have not been found in patients with pseudoxanthoma elasticum (PXE), another genetic multisystem ectopic calcification disorder caused by mutations in the ABCC6 gene. This study reports that ENPP1 mutations can also cause PXE with more favorable clinical outcomes. In addition, it was previously thought that plasma PPi levels correlate with vascular calcification severity. However, we here show that vascular calcification severity does not correlate with plasma PPi levels. The results suggest that in addition to PPi, the long-believed determinant of ectopic calcification, additional mechanisms may be at play in regulating ectopic calcification. [ABSTRACT FROM AUTHOR]