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ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) is a key regulator of extracellular inorganic pyrophosphate (PPi) and phosphate homeostasis. Biallelic loss-of-function variants in ENPP1 cause autosomal recessive hypophosphatemic rickets type 2 (ARHR2), characterized by renal phosphate wasting, elevated FGF23, and rickets. The condition overlaps with generalized arterial calcification of infancy but manifests predominantly as phosphate‐wasting bone disease.
Genetic evidence for ENPP1 in ARHR2 includes over 50 unrelated probands with homozygous or compound heterozygous ENPP1 loss-of-function variants ([PMID:24216977]). Variants include frameshift, nonsense, and canonical splice-site changes segregating in multiple families under an autosomal recessive model. A recurrent missense variant, c.1412A>G (p.Tyr471Cys), reduces enzymatic activity and has been reported in ARHR2 patients.
Functional studies demonstrate that Enpp1asj/asj knockout mice recapitulate key features of ARHR2, including hypophosphatemia, elevated plasma FGF23, rickets-like bone deformities, and reduced bone mineralization ([PMID:31805212]). Enzymatic assays confirm that loss-of-function ENPP1 variants abrogate PPi generation, driving phosphate wasting and rickets.
No studies have refuted the ARHR2 association; common ENPP1 polymorphisms linked to insulin resistance (e.g., K121Q) do not cause hypophosphatemic rickets, underscoring phenotype specificity. Experimental concordance across human and murine models supports a loss-of-function mechanism without evidence of dominant-negative effects.
In summary, biallelic ENPP1 pathogenic variants definitively underlie ARHR2 via loss of PPi-mediated inhibition of phosphate clearance and elevated FGF23. ENPP1 enzyme replacement and targeted therapies restoring PPi hold diagnostic and therapeutic promise. Key take-home: Genetic testing for ENPP1 should be standard in unexplained hereditary phosphate‐wasting rickets.
Gene–Disease AssociationDefinitiveOver 50 unrelated probands, biallelic LoF segregation in multiple families, concordant murine knockout models Genetic EvidenceStrongOver 50 ARHR probands with biallelic LoF ENPP1 variants across multiple families Functional EvidenceModerateEnpp1asj/asj mice recapitulate ARHR2 phenotype; enzymatic assays confirm loss of PPi generation |