Paediatric Rheumatology
Functional characterisation of a novel homozygous p.Y227C ADA2 variant in a child with deficiency of adenosine deaminase type 2
Y. Hong1, S. Dijkhuis2, C. Papadopoulou3, E. Omoyinmi4, A. Burleigh5, P. Brogan6, D. Eleftheriou7
- Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, UK. y.hong@ucl.ac.uk
- Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, UK.
- Paediatric Rheumatology Department, Great Ormond Hospital, London, UK.
- Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, UK.
- Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, UK.
- Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, UK.
- Infection, Immunity and Inflammation Department, University College London Great Ormond Street Institute of Child Health, London, UK.
CER19115
Paediatric Rheumatology
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PMID: 42207579 [PubMed]
Received: 17/07/2025
Accepted : 12/01/2026
In Press: 21/05/2026
Abstract
OBJECTIVES:
Deficiency of adenosine deaminase 2 (DADA2) is a rare inflammatory disorder caused by biallelic loss-of-function mutations in ADA2. We sought to functionally characterise a novel homozygous ADA2 variant, p.Y227C (c.680A>G), identified in a six-year-old patient presenting with recurrent fevers, erythema nodosum, and tumor necrosis factor (TNF) inhibitor-responsive myositis.
METHODS:
Monocyte-derived macrophages from the patient were analysed for ADA2 protein expression, enzymatic activity, and TNFα secretion. To model the inflammatory phenotype in vitro, THP-1 cells were engineered to express the p.Y227C variant. Lentiviral gene correction with wild-type ADA2 was performed to assess rescue of enzymatic function and inflammatory responses.
RESULTS:
Patient-derived macrophages exhibited markedly reduced ADA2 protein levels and enzymatic activity, accompanied by increased TNFα secretion. THP-1 cells expressing the p.Y227C variant recapitulated this proinflammatory phenotype. Lentiviral reconstitution with wild-type ADA2 restored protein expression and enzymatic activity and normalised TNFα release.
CONCLUSIONS:
The p.Y227C ADA2 variant is pathogenic and promotes inflammation through loss of ADA2 function. Functional rescue following gene correction confirms the causal role of this mutation and underscores the therapeutic potential of restoring ADA2 activity in DADA2.
