Early-onset stroke and vasculopathy associated with mutations in ADA2


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Early-onset stroke and vasculopathy associated with mutations in ADA2
N Engl J Med
Zhou Q., Yang D., Ombrello A. K., Zavialov A. V., Toro C., Zavialov A. 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., 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.
1533-4406 (Electronic)
Statut éditorial
Date de publication
Zhou, Qing
Yang, Dan
Ombrello, Amanda K
Zavialov, Andrey V
Toro, Camilo
Zavialov, Anton V
Stone, Deborah L
Chae, Jae Jin
Rosenzweig, Sergio D
Bishop, Kevin
Barron, Karyl S
Kuehn, Hye Sun
Hoffmann, Patrycja
Negro, Alejandra
Tsai, Wanxia L
Cowen, Edward W
Pei, Wuhong
Milner, Joshua D
Silvin, Christopher
Heller, Theo
Chin, David T
Patronas, Nicholas J
Barber, John S
Lee, Chyi-Chia R
Wood, Geryl M
Ling, Alexander
Kelly, Susan J
Kleiner, David E
Mullikin, James C
Ganson, Nancy J
Kong, Heidi H
Hambleton, Sophie
Candotti, Fabio
Quezado, Martha M
Calvo, Katherine R
Alao, Hawwa
Barham, Beverly K
Jones, Anne
Meschia, James F
Worrall, Bradford B
Kasner, Scott E
Rich, Stephen S
Goldbach-Mansky, Raphaela
Abinun, Mario
Chalom, Elizabeth
Gotte, Alisa C
Punaro, Marilynn
Pascual, Virginia
Verbsky, James W
Torgerson, Troy R
Singer, Nora G
Gershon, Timothy R
Ozen, Seza
Karadag, Omer
Fleisher, Thomas A
Remmers, Elaine F
Burgess, Shawn M
Moir, Susan L
Gadina, Massimo
Sood, Raman
Hershfield, Michael S
Boehm, Manfred
Kastner, Daniel L
Aksentijevich, Ivona
Z99 HG999999/Intramural NIH HHS/
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
N Engl J Med. 2014 Mar 6;370(10):911-20. doi: 10.1056/NEJMoa1307361. Epub 2014 Feb 19.
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.).
Adenosine Deaminase/*deficiency/*genetics, Age of Onset, Animals, Disease Models, Animal, Endothelium, Vascular/pathology, Female, Fever/genetics, Humans, Intercellular Signaling Peptides and Proteins/*deficiency/*genetics, Male, *Mutation, Pedigree, Polyarteritis Nodosa/genetics, Sequence Analysis, DNA, Skin/pathology, Stroke/*genetics, Vascular Diseases/*genetics, Vasculitis/genetics/pathology, Zebrafish
Création de la notice
01/11/2017 11:29
Dernière modification de la notice
20/08/2019 15:31
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