Comparison of disease phenotypes and mechanistic insight on causal variants in patients with DADA2

Liang Chen, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Anna Mamutova, Federal State Autonomous Institution "National Medical Research Center for Children's Health" of the Ministry of Health of the Russian Federation, Moscow, Russia.
Anna Kozlova, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
Elena Latysheva, NRC Institute of Immunology FMBA of Russia, Moscow, Russia.
Frolov Evgeny, NRC Institute of Immunology FMBA of Russia, Moscow, Russia.
Tatiana Latysheva, NRC Institute of Immunology FMBA of Russia, Moscow, Russia.
Kirill Savostyanov, Federal State Autonomous Institution "National Medical Research Center for Children's Health" of the Ministry of Health of the Russian Federation, Moscow, Russia.
Alexander Pushkov, Federal State Autonomous Institution "National Medical Research Center for Children's Health" of the Ministry of Health of the Russian Federation, Moscow, Russia.
Ilya Zhanin, Federal State Autonomous Institution "National Medical Research Center for Children's Health" of the Ministry of Health of the Russian Federation, Moscow, Russia.
Elena Raykina, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
Maria Kurnikova, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
Irina Mersiyanova, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
Craig D. Platt, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Hyuk Jee, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.

Document Type

Article

Publication Date

9-1-2023

Journal Title

The Journal of allergy and clinical immunology

MeSH Headings

Humans; Adenosine Deaminase (genetics); Intercellular Signaling Peptides and Proteins (genetics); Phenotype; Vasculitis; Mutation

Abstract

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) results in heterogeneous manifestations including systemic vasculitis and red cell aplasia. The basis of different disease phenotypes remains incompletely defined. OBJECTIVE: We sought to further delineate disease phenotypes in DADA2 and define the mechanistic basis of ADA2 variants. METHODS: We analyzed the clinical features and ADA2 variants in 33 patients with DADA2. We compared the transcriptomic profile of 14 patients by bulk RNA sequencing. ADA2 variants were expressed experimentally to determine impact on protein production, trafficking, release, and enzymatic function. RESULTS: Transcriptomic analysis of PBMCs from DADA2 patients with the vasculitis phenotype or pure red cell aplasia phenotype exhibited similar upregulation of TNF, type I interferon, and type II interferon signaling pathways compared with healthy controls. These pathways were also activated in 3 asymptomatic individuals with DADA2. Analysis of ADA2 variants, including 7 novel variants, showed different mechanisms of functional disruption including (1) unstable transcript leading to RNA degradation; (2) impairment of ADA2 secretion because of retention in the endoplasmic reticulum; (3) normal expression and secretion of ADA2 that lacks enzymatic function; and (4) disruption of the N-terminal signal peptide leading to cytoplasmic localization of unglycosylated protein. CONCLUSIONS: Transcriptomic signatures of inflammation are observed in patients with different disease phenotypes, including some asymptomatic individuals. Disease-associated ADA2 variants affect protein function by multiple mechanisms, which may contribute to the clinical heterogeneity of DADA2.

First Page

771

Last Page

782

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