NT5E Mutations and Arterial Calcifications

被引：344

作者：

St Hilaire, Cynthia ^{[2
]}

Ziegler, Shira G.

Markello, Thomas C. ^{[1
]}

Brusco, Alfredo ^{[4
,5
]}

Groden, Catherine ^{[1
]}

Gill, Fred ^{[3
]}

Carlson-Donohoe, Hannah

Lederman, Robert J. ^{[2
]}

Chen, Marcus Y. ^{[2
]}

Yang, Dan ^{[2
]}

Siegenthaler, Michael P. ^{[2
]}

Arduino, Carlo ^{[4
,5
]}

Mancini, Cecilia ^{[4
,5
]}

Freudenthal, Bernard ^{[6
,7
]}

Stanescu, Horia C. ^{[6
,7
]}

Zdebik, Anselm A. ^{[6
,7
]}

Chaganti, R. Krishna ^{[8
]}

Nussbaum, Robert L. ^{[9
]}

Kleta, Robert ^{[6
,7
]}

Gahl, William A. ^{[1
]}

Boehm, Manfred ^{[2
]}

机构：

[1] NHGRI, NIH Undiagnosed Dis Program, NIH, Bethesda, MD 20892 USA

[2] NHLBI, NIH, Bethesda, MD 20892 USA

[3] NIH, Off Rare Dis Res, Ctr Clin, Bethesda, MD 20892 USA

[4] Direz Univ Med Genet, Azienda Osped Univ San Giovanni Battista, Turin, Italy

[5] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy

[6] UCL, Dept Med, London WC1E 6BT, England

[7] UCL, Dept Physiol, London WC1E 6BT, England

[8] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[9] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2011年 / 364卷 / 05期

基金：

美国国家卫生研究院;

关键词：

NONSPECIFIC ALKALINE-PHOSPHATASE; VASCULAR CALCIFICATION; ADENOSINE; INFANCY; ENPP1; CELLS;

D O I：

10.1056/NEJMoa0912923

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Arterial calcifications are associated with increased cardiovascular risk, but the genetic basis of this association is unclear. METHODS We performed clinical, radiographic, and genetic studies in three families with symptomatic arterial calcifications. Single-nucleotide-polymorphism analysis, targeted gene sequencing, quantitative polymerase-chain-reaction assays, Western blotting, enzyme measurements, transduction rescue experiments, and in vitro calcification assays were performed. RESULTS We identified nine persons with calcifications of the lower-extremity arteries and hand and foot joint capsules: all five siblings in one family, three siblings in another, and one patient in a third family. Serum calcium, phosphate, and vitamin D levels were normal. Affected members of Family 1 shared a single 22.4-Mb region of homozygosity on chromosome 6 and had a homozygous nonsense mutation (c.662C -> A, p.S221X) in NT5E, encoding CD73, which converts AMP to adenosine. Affected members of Family 2 had a homozygous missense mutation (c.1073G -> A, p.C358Y) in NT5E. The proband of Family 3 was a compound heterozygote for c.662C -> A and c.1609dupA (p.V537fsX7). All mutations found in the three families result in nonfunctional CD73. Cultured fibroblasts from affected members of Family 1 showed markedly reduced expression of NT5E messenger RNA, CD73 protein, and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals. Genetic rescue experiments normalized the CD73 and alkaline phosphatase activity in patients' cells, and adenosine treatment reduced the levels of alkaline phosphatase and calcification. CONCLUSIONS We identified mutations in NT5E 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.

引用

页码：432 / 442

页数：11

共 29 条

[1] Fibronectin enhances in vitro vascular calcification by promoting osteoblastic differentiation of vascular smooth muscle cells via ERK pathway [J].