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. Author manuscript; available in PMC: 2024 May 1.
Published in final edited form as: Annu Rev Pathol. 2023 Oct 23;19:507–540. doi: 10.1146/annurev-pathmechdis-051222-121126

Figure 1.

Figure 1

Metabolic diseases due to homozygous defects in extracellular purinergic metabolism. The liver-associated transmembrane transporter ABCC6 [adenosine triphosphate (ATP)-binding cassette subfamily C member 6] exports ATP into the extracellular space, which is then metabolized by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) into adenosine monophosphate (AMP) and pyrophosphate (PPi). AMP is metabolized into adenosine and phosphate (Pi) by 5′-nucleotidase (CD73), and PPi is metabolized into Pi by tissue-nonspecific alkaline phosphatase (TNAP). Pi promotes, and PPi inhibits, hydroxyapatite, which constitutes the hard matrix of bone and ectopic calcifications in soft tissue. Pathogenic variants in ENPP1 and ABCC6 reduce extracellular plasma (PPi) to 10% and 30% of normal, respectively, inducing generalized calcification of infancy (GACI), in which approximately 50% of afflicted infants will succumb to life-threatening aortic and arterial calcifications. Those that survive will almost invariably exhibit phosphate wasting rickets in childhood, called autosomal recessive hypophosphatemic rickets type 2 (ARHR2).