Document Detail

Early-onset stroke and vasculopathy associated with mutations in ADA2.
MedLine Citation:
PMID:  24552284     Owner:  NLM     Status:  MEDLINE    
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.).
Qing Zhou; Dan Yang; Amanda K Ombrello; Andrey V Zavialov; Camilo Toro; Anton V Zavialov; Deborah L Stone; Jae Jin Chae; Sergio D Rosenzweig; Kevin Bishop; Karyl S Barron; Hye Sun Kuehn; Patrycja Hoffmann; Alejandra Negro; Wanxia L Tsai; Edward W Cowen; Wuhong Pei; Joshua D Milner; Christopher Silvin; Theo Heller; David T Chin; Nicholas J Patronas; John S Barber; Chyi-Chia R Lee; Geryl M Wood; Alexander Ling; Susan J Kelly; David E Kleiner; James C Mullikin; Nancy J Ganson; Heidi H Kong; Sophie Hambleton; Fabio Candotti; Martha M Quezado; Katherine R Calvo; Hawwa Alao; Beverly K Barham; Anne Jones; James F Meschia; Bradford B Worrall; Scott E Kasner; Stephen S Rich; Raphaela Goldbach-Mansky; Mario Abinun; Elizabeth Chalom; Alisa C Gotte; Marilynn Punaro; Virginia Pascual; James W Verbsky; Troy R Torgerson; Nora G Singer; Timothy R Gershon; Seza Ozen; Omer Karadag; Thomas A Fleisher; Elaine F Remmers; Shawn M Burgess; Susan L Moir; Massimo Gadina; Raman Sood; Michael S Hershfield; Manfred Boehm; Daniel L Kastner; Ivona Aksentijevich
Related Documents :
24571724 - Constitutive activation of pka catalytic subunit in adrenal cushing's syndrome.
23391844 - Presence of the jak2 v617f mutation in a patient with chronic neutrophilic leukemia and...
23952244 - Asxl1 mutations are infrequent in young patients with primary acute myeloid leukemia an...
24594054 - Genetic testing in the management of relatives of patients with hypertrophic cardiomyop...
19930154 - Phenotype and genotype in females with pou3f4 mutations.
9358014 - Ethnic differences in the hfe codon 282 (cys/tyr) polymorphism.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2014-02-19
Journal Detail:
Title:  The New England journal of medicine     Volume:  370     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2014 Mar 
Date Detail:
Created Date:  2014-03-06     Completed Date:  2014-03-18     Revised Date:  2014-10-14    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  911-20     Citation Subset:  AIM; IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Adenosine Deaminase / deficiency*,  genetics*
Age of Onset
Disease Models, Animal
Endothelium, Vascular / pathology
Fever / genetics
Intercellular Signaling Peptides and Proteins / deficiency*,  genetics*
Polyarteritis Nodosa / genetics
Sequence Analysis, DNA
Skin / pathology
Stroke / genetics*
Vascular Diseases / genetics*
Vasculitis / genetics,  pathology
Grant Support
Reg. No./Substance:
0/Intercellular Signaling Peptides and Proteins; EC Deaminase; EC protein, human
Comment In:
N Engl J Med. 2014 Jul 31;371(5):478-9   [PMID:  25075846 ]
N Engl J Med. 2014 Jul 31;371(5):480-1   [PMID:  25075844 ]
Nat Rev Rheumatol. 2014 Jun;10(6):323-4   [PMID:  24818673 ]
N Engl J Med. 2014 Jul 31;371(5):478   [PMID:  25075845 ]
N Engl J Med. 2014 Jul 31;371(5):478-80   [PMID:  25075847 ]
N Engl J Med. 2014 Jul 31;371(5):480   [PMID:  25075848 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  The Adsorption Behaviour of Ionic Surfactants and their Mixtures with Nonionic Polymers and with Pol...
Next Document:  Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.