Early-onset stroke and vasculopathy associated with mutations in ADA2
Details
Serval ID
serval:BIB_733A47C9AE63
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Early-onset stroke and vasculopathy associated with mutations in ADA2
Journal
N Engl J Med
ISSN
1533-4406 (Electronic)
ISSN-L
0028-4793
Publication state
Published
Issued date
2014
Volume
370
Number
10
Pages
911-20
Language
english
Notes
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
eng
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.
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
eng
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.
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.).
Keywords
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
Pubmed
Create date
01/11/2017 10:29
Last modification date
20/08/2019 14:31