| Title: | Dominant negative ADA2 mutations cause ADA2 deficiency in heterozygous carriers |
| Journal: | Journal of Experimental Medicine |
| Published: | 27 Aug 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40864493/ |
| DOI: | https://doi.org/10.1084/jem.20250499 |
| URL: | https://rupress.org/jem/article-pdf/222/11/e20250499/1949486/jem_20250499.pdf |
Publication 19648
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Abstract
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.</p>
17 Keywords
- Adenosine Deaminase
- Adult
- Agammaglobulinemia
- Child
- Child, Preschool
- Female
- Genes, Dominant
- Hereditary Autoinflammatory Diseases
- Heterozygote
- Humans
- Intercellular Signaling Peptides and Proteins
- Male
- Mutation
- Mutation, Missense
- Pedigree
- Phenotype
- Severe Combined Immunodeficiency
18 Authors
- Marjon Wouters
- Lisa Ehlers
- Wout Van Eynde
- Meltem Ece Kars
- Selket Delafontaine
- Verena Kienapfel
- Mariia Dzhus
- Rik Schrijvers
- Petra De Haes
- Sofie Struyf
- Giorgia Bucciol
- Yuval Itan
- Alexandre Bolze
- Arnout Voet
- Anneleen Hombrouck
- Leen Moens
- Benson Ogunjimi
- Isabelle Meyts
1 Application
| Application ID | Title |
|---|---|
| 53074 | Identifying novel high-impact rare disease-causing mutations, genes and pathways in inflammatory bowel disease patients |
Enabling scientific discoveries that improve human health