Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets.
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.
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Bettina
B
Lorenz-Depiereux
Dirk
D
Schnabel
Dov
D
Tiosano
Gabriele
G
Häusler
Tim M
TM
Strom
D000293:Adolescent; D000595:Amino Acid Sequence; D002114:Calcinosis / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D053098:Familial Hypophosphatemic Rickets / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D005190:Family; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics*; D011755:Pyrophosphatases / Q000737:chemistry / Q000235:genetics*; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics
C000717427:FGF23 protein, human; C493554:SLC34A1 protein, human; C493562:SLC34A3 protein, human; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D000089703:Fibroblast Growth Factor-23; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases