Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).
Adenosine deaminase 2
DADA2
bone marrow failure
pure red cell aplasia
vasculitis
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
30
10
2019
revised:
07
12
2019
accepted:
27
12
2019
pubmed:
17
1
2020
medline:
20
2
2021
entrez:
17
1
2020
Statut:
ppublish
Résumé
Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.
Sections du résumé
BACKGROUND
Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable.
OBJECTIVE
We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation.
METHODS
Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum.
RESULTS
We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function.
CONCLUSIONS
Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.
Identifiants
pubmed: 31945408
pii: S0091-6749(20)30030-0
doi: 10.1016/j.jaci.2019.12.908
pmc: PMC7282972
mid: NIHMS1549750
pii:
doi:
Substances chimiques
Intercellular Signaling Peptides and Proteins
0
ADA2 protein, human
EC 3.5.4.4
Adenosine Deaminase
EC 3.5.4.4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1664-1672.e10Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR073201
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR070253
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR065538
Pays : United States
Organisme : Versus Arthritis
ID : 21791
Pays : United Kingdom
Organisme : NIAMS NIH HHS
ID : K08 AR074562
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR075906
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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