PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathicinfantile arterial calcification

Inogranic pyrophosphate (PPi) inhibits hydroxyapatite deposition, and mice deficient in the PPi-generating nucleoside triphosphate pyrophosphohydrolas e (NTPPPH) Plasma cell membrane glycoprotein-l (PC-1) develop peri-articula r and arterial calcification in early life. In idiopathic infantile arteria l calcification (IIAC), hydroxyapatite deposition and smooth muscle cell (S MC) proliferation occur, sometimes associated with peri-articular calcifica tion. Thus, we assessed PC-1 expression and PPI metabolism in a 25-month-ol d boy with IIAC and peri-articular calcifications, Plasma PC-1 was <1 ng/ml by enzyme-linked immunosorbent assay in the proband, but 10 to 30 ng/ml in unaffected family members and controls. PC-1 functioned to raise extracell ular PPI in cultured aortic SMCs, However, PC-1 was sparse in temporal arte ry lesion SMCs in the proband, unlike the case for SMCs in atherosclerotic carotid artery lesions of unrelated adults. Proband plasma and explant-cult ured dermal fibroblast NTPPPH and PPi were markedly decreased. The proband was heterozygous at the PC-1 locus, and sizes of PC-1 mRNA and polypeptide, and the PC-1 mRNA-coding region sequence were normal in proband fibroblast s. However, immunoreactive PC-1 protein was relatively sparse in proband fi broblasts, In conclusion, deficient extracellular PPi and a deficiency of P C-1 NTPPPH activity can be associated with human infantile arterial and per i-articular calcification, and may help explain the sharing of certain phen otypic features between some IIAC patients and PC-1-deficient mice.