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Researchers at the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute, along with international collaborators, have uncovered the genetic cause of a disease they've called arterial calcification due to deficiency of CD73 — or ACDC — using million-SNP array and targeted gene expression analyses of affected individuals and their relatives. Working through the National Institutes of Health's Undiagnosed Diseases Program, the team also identified two potential ACDC therapeutic targets and a previously unreported role for adenosine in vasculature, which it suggests could have implications for more common disorders, such as atherosclerosis and osteoporosis.

"Finding the cause for this disorder was a major advance in biology," NHGRI Clinical Director William Gahl told reporters in a briefing. NHLBI's Manfred Boehm added that the team "had a key advantage in reaching a diagnosis in this case: involvement of many family members who could contribute samples for our testing."

Sisters Louise Benge and Paula Allen are among the first nine patients to be diagnosed with ACDC, a rare, recessive disorder characterized by painful, heterotrophic arterial calcifications in the lower extremities.

Using million-SNP arrays, Gahl's team identified runs of homozygosity that span 92 genes in Allen, Benge, and their three affected siblings. With maternal and paternal genetic data in hand, the team homed in on a promising candidate gene, NT5E, in which it identified nonsense mutations in each affected sibling, and not in their unaffected parents. Meanwhile, Boehm's group found markedly reduced levels of the NT5E protein product CD73, which is involved in adenosine production, in cultured fibroblasts from each of the five affected siblings.

As it turns out, adenosine prevents arterial calcifications, Boehm said. Reduced levels of adenosine in ACDC patients leads to the elevated activity of a tissue non-specific alkaline phosphatase enzyme, which plays a role in the production of the calcification agent pyrophosphate. "In short, deficiency of CD73 leads to these arterial calcifications," Boehm said, adding that two main therapeutic targets emerged in his team's investigations: adenosine and alkaline phosphatase.

Gahl and Boehm's team eventually learned of other patients — three affected siblings in an Italian family and an affected proband in the UK — who reported similar symptoms. Investigators at the University of Turin identified homozygous missense NT5E mutations in the Italian siblings, while researchers at the Great Ormond Street Hospital in London found that its proband is a compound heterozygote for NT5E mutations that produced non-functional CD73 as a result of a premature stop codon. The international team reported its analyses of nine total affected individuals in the New England Journal of Medicine last month.

Gahl said this study not only provided "hope for future treatment" options for ACDC, but that it may also have implications for other disorders.

"We now identify that adenosine regulates … alkaline phosphatase," Boehm added. "By identifying the exact pathway, we may obtain more knowledge about the connection between osteoporosis and atherosclerosis, which will also lead us, hopefully, to a more targeted treatment for one component or the other."

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