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.
Lorenz-Depiereux
Bettina
B
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Schnabel
Dirk
D
Tiosano
Dov
D
Häusler
Gabriele
G
Strom
Tim M
TM
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