Genetics of vascular calcification.

Recessive mutations in the NTE5 gene were recently described in lower-extremity vascular calcification. ENPP1 mutations were previously described in a severe disorder of vascular calcification in infancy. Together these data support that extracellular adenosine and pyrophosphate are essential components of the pathways in vascular disease. Arterial calcification by impairing blood flow and reducing vessel compliance increases the risk for vascular disease in aging, diabetes, and renal disease. Whether or not arterial calcification is an active participant in vascular disease, it is readily identifiable, providing the rationale for less invasive means of coronary artery screening. The molecular mechanisms governing vascular calcification overlap substantially with the mechanisms of bone formation. The recent work of St Hilaire et al1 demonstrates that mutations in the gene encoding CD73, an ectonucleotidase, cause peripheral arterial calcification. The NT5E gene encodes the cell surface protein CD73, which catalyzes the conversion of AMP to adenosine and inorganic phosphate (Figure). The genetic defect was identified using a single family with 5 affected individuals, ages 44 to 54 years, each of whom had significant vascular calcification of the lower extremities. Because their parents were third cousins, it was reasonable to assume that a homozygous recessive gene was responsible. Using a genotyping array containing a million single nucleotide polymorphisms, the authors identified a single region of homozygosity shared among the affected siblings. This region spanned 22 MB and contained 92 genes, including the NT5E gene. NT5E encodes the second enzyme in the pathway that converts extracellular ATP to adenosine. The first enzyme in this pathway, ENPP1 (also known as NPP1), was previously implicated in a more severe calcification disorder known as idiopathic infantile arterial calcification.2 Idiopathic infantile arterial calcification is characterized by calcification of the internal elastic lamina. Also a recessive disorder, the most severe mutations are those that associate with loss of enzymatic function. ENPP1 encodes an ectonucleotide pyrophosphatase that utilizes extracellular ATP as its substrate, generating AMP and pyrophosphate. Patients with idiopathic infantile arterial calcification often die in infancy, with more extensive vascular calcification afflicting nearly all arterial beds, including the coronary arteries. The genetic findings in the 3 families described by St Hilaire are compelling in that a truncating mutation was found in the index family (p.S221X).1 A second unrelated family was homozygous for a missense change p.C358Y, and a single affected individual in a third family was a compound heterozygote with the same nonsense mutation from family 1 and a novel insertion that led to a frameshift and stop codon. None of the heterozygous parents displayed features of calcification, suggesting that a threshold of enzymatic activity is sufficient to prevent vascular calcification.