Dominant negative <i>ADA2</i> mutations cause ADA2 deficiency in heterozygous carriers
Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype, which encompasses vasculopathy and hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. We investigated the effect of these and additional reported ADA2 missense variants on ADA2 protein expression, secretion, and enzymatic activity. Our studies indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2.
Authors
- Arnout R. D. Voet (ORCID: https://orcid.org/0000-0002-3329-2703)
- Benson Ogunjimi (ORCID: https://orcid.org/0000-0002-0831-2063)
- Leen Moens (ORCID: https://orcid.org/0000-0002-5347-6526)
- Yuval Itan (ORCID: https://orcid.org/0000-0003-4966-3238)
- Petra De Haes (ORCID: https://orcid.org/0000-0001-6503-6088)
- Rik Schrijvers (ORCID: https://orcid.org/0000-0002-4261-6220)
- Mariia Dzhus (ORCID: https://orcid.org/0000-0002-2077-4295)
- Isabelle Meyts (ORCID: https://orcid.org/0000-0003-1214-0302)
- Alexandre Bolze (ORCID: https://orcid.org/0000-0001-7399-2766)
- Meltem Ece Kars (ORCID: https://orcid.org/0000-0001-5922-5608)
- Anneleen Hombrouck (ORCID: https://orcid.org/0009-0003-5236-6063)
- Selket Delafontaine (ORCID: https://orcid.org/0000-0002-8985-8155)
- Giorgia Bucciol (ORCID: https://orcid.org/0000-0001-5004-0738)
- Marjon Wouters (ORCID: https://orcid.org/0000-0002-4675-1665)
- Lisa Ehlers (ORCID: https://orcid.org/0000-0001-8737-001X)
- Sofie Struyf (ORCID: https://orcid.org/0000-0003-4558-0769)
- Verena Kienapfel (ORCID: https://orcid.org/0009-0002-5476-2257)
- Wout Van Eynde (ORCID: https://orcid.org/0000-0001-9426-862X)
Institutions
- Rega Institute for Medical Research (BE)
- Universitair Ziekenhuis Leuven (BE)
- Leibniz Association (DE)
- Humboldt-Universität zu Berlin (DE)
- German Rheumatism Research Centre (DE)
- Antwerp University Hospital (BE)
- Child Health and Development Institute (US)
- Infectious Diseases Institute (UG)
- German Centre for Cardiovascular Research (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Helix (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
- KU Leuven (BE)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-07-30
- DOI
- https://doi.org/10.1084/jem.20250499
- Citations
- 3
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- Jeffrey Modell Foundation
- Icahn School of Medicine at Mount Sinai
- CSL Behring
- Charité – Universitätsmedizin Berlin
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Vlaamse regering
- Berlin Institute of Health
- European Research Council
- National Center for Advancing Translational Sciences