Early-onset stroke and vasculopathy associated with mutations in ADA2

Q. Zhou, D. Yang, A. K. Ombrello, Andrey V. Zavialov, C. Toro, Anton V. Zavialov, D. L. Stone, J. J. Chae, S. D. Rosenzweig, K. Bishop, K. S. Barron, H. S. Kuehn, P. Hoffmann, A. Negro, W. L. Tsai, E. W. Cowen, W. Pei, J. D. Milner, C. Silvin, T. HellerD. T. Chin, N. J. Patronas, J. S. Barber, C. C R Lee, G. M. Wood, A. Ling, S. J. Kelly, D. E. Kleiner, J. C. Mullikin, N. J. Ganson, H. H. Kong, S. Hambleton, F. Candotti, M. M. Quezado, K. R. Calvo, H. Alao, B. K. Barham, A. Jones, J. F. Meschia, B. B. Worrall, S. E. Kasner, S. S. Rich, R. Goldbach-Mansky, M. Abinun, E. Chalom, A. C. Gotte, M. Punaro, V. Pascual, J. W. Verbsky, T. R. Torgerson, N. G. Singer, T. R. Gershon, S. Ozen, O. Karadag, T. A. Fleisher, E. F. Remmers, S. M. Burgess, S. L. Moir, M. Gadina, R. Sood, M. S. Hershfield, M. Boehm, D. L. Kastner, I. Aksentijevich

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Abstract

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.)

Original languageEnglish (US)
Pages (from-to)911-920
Number of pages10
JournalNew England Journal of Medicine
Volume370
Issue number10
DOIs
StatePublished - 2014

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Adenosine Deaminase
Stroke
Mutation
Vasculitis
Chromosomes
Polyarteritis Nodosa
Zebrafish
Phenotype
Endothelial Cells
Exome
Lacunar Stroke
Morpholinos
U937 Cells
Skin
Intracranial Hemorrhages
National Institutes of Health (U.S.)
Enzyme Assays
Exanthema
Neutropenia
Immunoblotting

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhou, Q., Yang, D., Ombrello, A. K., Zavialov, A. V., Toro, C., Zavialov, A. V., ... Aksentijevich, I. (2014). Early-onset stroke and vasculopathy associated with mutations in ADA2. New England Journal of Medicine, 370(10), 911-920. https://doi.org/10.1056/NEJMoa1307361

Early-onset stroke and vasculopathy associated with mutations in ADA2. / Zhou, Q.; Yang, D.; Ombrello, A. K.; Zavialov, Andrey V.; Toro, C.; Zavialov, Anton V.; Stone, D. L.; Chae, J. J.; Rosenzweig, S. D.; Bishop, K.; Barron, K. S.; Kuehn, H. S.; Hoffmann, P.; Negro, A.; Tsai, W. L.; Cowen, E. W.; Pei, W.; Milner, J. D.; Silvin, C.; Heller, T.; Chin, D. T.; Patronas, N. J.; Barber, J. S.; Lee, C. C R; Wood, G. M.; Ling, A.; Kelly, S. J.; Kleiner, D. E.; Mullikin, J. C.; Ganson, N. J.; Kong, H. H.; Hambleton, S.; Candotti, F.; Quezado, M. M.; Calvo, K. R.; Alao, H.; Barham, B. K.; Jones, A.; Meschia, J. F.; Worrall, B. B.; Kasner, S. E.; Rich, S. S.; Goldbach-Mansky, R.; Abinun, M.; Chalom, E.; Gotte, A. C.; Punaro, M.; Pascual, V.; Verbsky, J. W.; Torgerson, T. R.; Singer, N. G.; Gershon, T. R.; Ozen, S.; Karadag, O.; Fleisher, T. A.; Remmers, E. F.; Burgess, S. M.; Moir, S. L.; Gadina, M.; Sood, R.; Hershfield, M. S.; Boehm, M.; Kastner, D. L.; Aksentijevich, I.

In: New England Journal of Medicine, Vol. 370, No. 10, 2014, p. 911-920.

Research output: Contribution to journalArticle

Zhou, Q, Yang, D, Ombrello, AK, Zavialov, AV, Toro, C, Zavialov, AV, 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, CCR, 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 2014, 'Early-onset stroke and vasculopathy associated with mutations in ADA2', New England Journal of Medicine, vol. 370, no. 10, pp. 911-920. https://doi.org/10.1056/NEJMoa1307361
Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. New England Journal of Medicine. 2014;370(10):911-920. https://doi.org/10.1056/NEJMoa1307361
Zhou, Q. ; Yang, D. ; Ombrello, A. K. ; Zavialov, Andrey V. ; Toro, C. ; Zavialov, Anton V. ; Stone, D. L. ; Chae, J. J. ; Rosenzweig, S. D. ; Bishop, K. ; Barron, K. S. ; Kuehn, H. S. ; Hoffmann, P. ; Negro, A. ; Tsai, W. L. ; Cowen, E. W. ; Pei, W. ; Milner, J. D. ; Silvin, C. ; Heller, T. ; Chin, D. T. ; Patronas, N. J. ; Barber, J. S. ; Lee, C. C R ; Wood, G. M. ; Ling, A. ; Kelly, S. J. ; Kleiner, D. E. ; Mullikin, J. C. ; Ganson, N. J. ; Kong, H. H. ; Hambleton, S. ; Candotti, F. ; Quezado, M. M. ; Calvo, K. R. ; Alao, H. ; Barham, B. K. ; Jones, A. ; Meschia, J. F. ; Worrall, B. B. ; Kasner, S. E. ; Rich, S. S. ; Goldbach-Mansky, R. ; Abinun, M. ; Chalom, E. ; Gotte, A. C. ; Punaro, M. ; Pascual, V. ; Verbsky, J. W. ; Torgerson, T. R. ; Singer, N. G. ; Gershon, T. R. ; Ozen, S. ; Karadag, O. ; Fleisher, T. A. ; Remmers, E. F. ; Burgess, S. M. ; Moir, S. L. ; Gadina, M. ; Sood, R. ; Hershfield, M. S. ; Boehm, M. ; Kastner, D. L. ; Aksentijevich, I. / Early-onset stroke and vasculopathy associated with mutations in ADA2. In: New England Journal of Medicine. 2014 ; Vol. 370, No. 10. pp. 911-920.
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title = "Early-onset stroke and vasculopathy associated with mutations in ADA2",
abstract = "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.)",
author = "Q. Zhou and D. Yang and Ombrello, {A. K.} and Zavialov, {Andrey V.} and C. Toro and Zavialov, {Anton V.} and Stone, {D. L.} and Chae, {J. J.} and Rosenzweig, {S. D.} and K. Bishop and Barron, {K. S.} and Kuehn, {H. S.} and P. Hoffmann and A. Negro and Tsai, {W. L.} and Cowen, {E. W.} and W. Pei and Milner, {J. D.} and C. Silvin and T. Heller and Chin, {D. T.} and Patronas, {N. J.} and Barber, {J. S.} and Lee, {C. C R} and Wood, {G. M.} and A. Ling and Kelly, {S. J.} and Kleiner, {D. E.} and Mullikin, {J. C.} and Ganson, {N. J.} and Kong, {H. H.} and S. Hambleton and F. Candotti and Quezado, {M. M.} and Calvo, {K. R.} and H. Alao and Barham, {B. K.} and A. Jones and Meschia, {J. F.} and Worrall, {B. B.} and Kasner, {S. E.} and Rich, {S. S.} and R. Goldbach-Mansky and M. Abinun and E. Chalom and Gotte, {A. C.} and M. Punaro and V. Pascual and Verbsky, {J. W.} and Torgerson, {T. R.} and Singer, {N. G.} and Gershon, {T. R.} and S. Ozen and O. Karadag and Fleisher, {T. A.} and Remmers, {E. F.} and Burgess, {S. M.} and Moir, {S. L.} and M. Gadina and R. Sood and Hershfield, {M. S.} and M. Boehm and Kastner, {D. L.} and I. Aksentijevich",
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TY - JOUR

T1 - Early-onset stroke and vasculopathy associated with mutations in ADA2

AU - Zhou, Q.

AU - Yang, D.

AU - Ombrello, A. K.

AU - Zavialov, Andrey V.

AU - Toro, C.

AU - Zavialov, Anton V.

AU - Stone, D. L.

AU - Chae, J. J.

AU - Rosenzweig, S. D.

AU - Bishop, K.

AU - Barron, K. S.

AU - Kuehn, H. S.

AU - Hoffmann, P.

AU - Negro, A.

AU - Tsai, W. L.

AU - Cowen, E. W.

AU - Pei, W.

AU - Milner, J. D.

AU - Silvin, C.

AU - Heller, T.

AU - Chin, D. T.

AU - Patronas, N. J.

AU - Barber, J. S.

AU - Lee, C. C R

AU - Wood, G. M.

AU - Ling, A.

AU - Kelly, S. J.

AU - Kleiner, D. E.

AU - Mullikin, J. C.

AU - Ganson, N. J.

AU - Kong, H. H.

AU - Hambleton, S.

AU - Candotti, F.

AU - Quezado, M. M.

AU - Calvo, K. R.

AU - Alao, H.

AU - Barham, B. K.

AU - Jones, A.

AU - Meschia, J. F.

AU - Worrall, B. B.

AU - Kasner, S. E.

AU - Rich, S. S.

AU - Goldbach-Mansky, R.

AU - Abinun, M.

AU - Chalom, E.

AU - Gotte, A. C.

AU - Punaro, M.

AU - Pascual, V.

AU - Verbsky, J. W.

AU - Torgerson, T. R.

AU - Singer, N. G.

AU - Gershon, T. R.

AU - Ozen, S.

AU - Karadag, O.

AU - Fleisher, T. A.

AU - Remmers, E. F.

AU - Burgess, S. M.

AU - Moir, S. L.

AU - Gadina, M.

AU - Sood, R.

AU - Hershfield, M. S.

AU - Boehm, M.

AU - Kastner, D. L.

AU - Aksentijevich, I.

PY - 2014

Y1 - 2014

N2 - 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.)

AB - 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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