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