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NT5E Mutations and Arterial Calcifications
Study Questions:
What genes are associated with familial, severe arterial calcifications?
Methods:
Clinical, radiographic, and genetic studies were performed in three families with symptomatic arterial calcifications. Single-nucleotide-polymorphism analysis, targeted gene sequencing, quantitative polymerase-chain-reaction, Western blotting, enzyme measurements, transduction rescue experiments, and in vitro calcification assays were performed.
Results:
Nine persons with severe calcifications of the lower-extremity arteries and hand and foot joint capsules were identified: all five siblings in one family, three siblings in another, and one patient in a third family. Mutations leading to inactivation of the gene, CD73, were found in all affected members. Fibroblasts cultured from affected patients showed reduced expression of CD73 and accumulation of calcium phosphate crystals, findings that were reversed when CD73 function was genetically restored.
Conclusions:
The authors concluded that mutations in NT5E were identified in members of three families with symptomatic arterial and joint calcifications. This gene encodes CD73, which converts AMP to adenosine, supporting a role for this metabolic pathway in inhibiting ectopic tissue calcification.
Perspective:
Arterial calcifications are associated with increased risk for vascular complications. Whether the calcium is playing a causal role in growth of the atherosclerotic plaque or secondarily deposited in advanced plaques is controversial. The current study analyzed patients with severe lower extremity vascular and extravascular calcifications, suggesting the responsible genetic defect leads to a primary calcium deposition abnormality, independent of serum calcium, phosphate, and vitamin D levels. The mechanism by which CD73 affects calcification is not clear, but may be related to indirect downregulation of pyrophosphate. This mechanism is important because it suggests possible therapeutic approaches to reduce vascular calcification, such as levamisole, bisphosphonates, and dipyridamole. Further studies are necessary to determine effectiveness of targeting this metabolic pathway to reduce ectopic calcium deposition.
Keywords: Mutation, Joint Capsule, Calcium Phosphates, Plaque, Atherosclerotic, Biomarkers, Vascular Calcification, Metabolic Networks and Pathways, Calcinosis, Vitamin D, Calcium
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