Novel disease caused by mutations in CD73 leads to vascular calcification in adults

Wednesday, October 26, 2011 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center	NHLBI	CLIN/CULT/AGING/DISPREV-25

* FARE Award Winner

Authors

• C St. Hilaire
• SG Ziegler
• T Markello
• A Bruscs
• C Groden
• F Gill
• H Carlson-Donohoe
• RJ Lederman
• MY Chen
• D Yan
• MP Siegenthaler
• C Arduino
• Cynth Mancini
• B Freudenthal
• HC Stanescu
• AA Zdebik
• R Krishna Chagant
• R Kleta
• WA Gahl
• M Boehm

Abstract

Vascular calcification is often a complication to diseases such as diabetes and chronic kidney disease, and is a predictor of premature death. We identified a novel, monogenetic disease in which individuals form arterial calcifications in their lower-extremity arteries. We identified three novel biallelic mutations in the NT5E gene in affected individuals. NT5E encodes for CD73, which converts extracellular AMP to adenosine. Adenosine acts as a signaling molecule by binding to one of the four adenosine receptors expressed on a wide range of cells; these patients are assumed to have reduced adenosine signaling. This is the first study that links extracellular adenosine signaling to pathological vascular calcification. We developed an in vitro calcification assay using patient specific CD73-deficient and control cells and show that CD73-deficient cells accumulate calcium phosphate crystals. Genetic rescue with lentivirus overexpressing wild type CD73 prevented calcification of CD73-deficient cells. Exogenous adenosine treatment reduced in vitro calcification, indicating the role of adenosine signaling in the etiology of this disease. Loss of CD73 function due to biallelic NT5E mutations represents a new autosomal recessive disorder of vascular calcification, revealing the critical role of adenosine in inhibiting ectopic calcification within specific vessels

back to top