Önen M. Ö., Everest E., Demirci T., Timuçin A. C., Yıldız M., Şahin S., ...Daha Fazla
TURKISH ARCHIVES OF PEDIATRICS, ss.1-12, 2026 (ESCI)
Özet
Objective: Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by biallelic pathogenic variations in the adenosine deaminase type 2 (ADA2) gene. The authors aimed to measure adenosine deaminase (ADA) activity in the patients with ADA2 variants and determine the consequences of the identified variants on protein stability.
Methods: The authors measured the total ADA activity in the peripheral blood mononuclear cells of 8 patients with ADA2 gene variants and 5 healthy controls using an ADA Activity Assay Kit. Additionally, the authors conducted a computational study involving stability analyses, 100 ns molecular dynamics simulations, and molecular mechanics Poisson–Boltzmann surface area analyses.
Results: Five patients had the homozygous NM_001282225.2:c.139G>A (p.Gly47Arg) variant, 2 patients had 2 heterozygous variants NM_001282225.2:c.139G>A(;)962G>A (p.Gly47Arg(;) Gly321Glu), and 1 of the patients had a novel heterozygous variant NM_001282225.2:c.467C>T (p.Ser156Leu) in the ADA2 gene. Total ADA activity was significantly lower in patients than in healthy controls (P = .0009). Moreover, ADA activity was tended to be lower in patients possessing 2 heterozygous variants c.139G>A(;)962G>A (p.Gly47Arg(;)Gly321Glu), than in patients with homozygous c.139G>A (p.Gly47Arg) (statistically not significant). The computational analysis investigating the combined impact of c.139G>A (p.Gly47Arg) and c.962G>A (p.Gly321Glu) on the catalytic activity of ADA2 showed that these variants, particularly when identified in the same patient, can interfere with dimerization of ADA2 protein.
Conclusion: Altogether, these results suggest that although both variants contribute altered ADA2 activity, c.962G>A (p.Gly321Glu) variant has a more prominent effect on the catalytic activity of ADA2 and in the pathophysiology of DADA2. Further, distinct ADA2 genotypes and overlapping phenotypic features highlight the complexity of genotype–phenotype correlations in DADA2.