Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets

Abstract

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization.

Figure 1

ENPP1 Mutations in Four Families with Autosomal-Recessive Hypophosphatemia The different clinical phenotypes are indicated by half filled boxes; light gray:GACI, dark gray:rickets and black:hypophosphatemia. DNA was available from all patients labeled with a DNA identifier. Patient 23320 and his son 24384 in family 4 carry the same homozygous ENPP1 mutation, but with different clinical outcome.

Figure 2

Position of ENPP1 Mutations Causing Hypophosphatemic Rickets or GACI Distribution of ENPP1 mutations. ENPP1 exons are represented as boxes 1-25. Mutations published previously in patients with GACI are indicated above the gene; mutations detected in this study are drawn below the gene. Functional domains are indicated by gray and hatched areas. TM:transmembrane domain, SO:somatomedin B-like domain. Asterisk:rs28933977.