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Early-onset stroke and vasculopathy associated with mutations in ADA2.

Publication ,  Journal Article
Zhou, Q; Yang, D; Ombrello, AK; Zavialov, AV; Toro, C; Zavialov, AV; Stone, DL; Chae, JJ; Rosenzweig, SD; Bishop, K; Barron, KS; Kuehn, HS ...
Published in: N Engl J Med
March 6, 2014

BACKGROUND: We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS: We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS: All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS: Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

March 6, 2014

Volume

370

Issue

10

Start / End Page

911 / 920

Location

United States

Related Subject Headings

  • Zebrafish
  • Vasculitis
  • Vascular Diseases
  • Stroke
  • Skin
  • Sequence Analysis, DNA
  • Polyarteritis Nodosa
  • Pedigree
  • Mutation
  • Male
 

Citation

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Chicago
ICMJE
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Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Stone, D. L., … Aksentijevich, I. (2014). Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med, 370(10), 911–920. https://doi.org/10.1056/NEJMoa1307361
Zhou, Qing, Dan Yang, Amanda K. Ombrello, Andrey V. Zavialov, Camilo Toro, Anton V. Zavialov, Deborah L. Stone, et al. “Early-onset stroke and vasculopathy associated with mutations in ADA2.N Engl J Med 370, no. 10 (March 6, 2014): 911–20. https://doi.org/10.1056/NEJMoa1307361.
Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Stone DL, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014 Mar 6;370(10):911–20.
Zhou, Qing, et al. “Early-onset stroke and vasculopathy associated with mutations in ADA2.N Engl J Med, vol. 370, no. 10, Mar. 2014, pp. 911–20. Pubmed, doi:10.1056/NEJMoa1307361.
Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee C-CR, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014 Mar 6;370(10):911–920.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

March 6, 2014

Volume

370

Issue

10

Start / End Page

911 / 920

Location

United States

Related Subject Headings

  • Zebrafish
  • Vasculitis
  • Vascular Diseases
  • Stroke
  • Skin
  • Sequence Analysis, DNA
  • Polyarteritis Nodosa
  • Pedigree
  • Mutation
  • Male