The following is a summary of “Comparison of disease phenotypes and mechanistic insight on causal variants in patients with DADA2,” published in the SEPTEMBER 2023 issue of Allergy & Immunology by Chen, et al.
Adenosine deaminase 2 deficiency (DADA2) leads to a range of clinical symptoms, such as systemic vasculitis and red cell aplasia. However, the underlying reasons for the diverse disease phenotypes are not fully understood. For a study, researchers sought to clarify the disease phenotypes in DADA2 and to uncover the mechanisms behind ADA2 variants.
The study involved the examination of clinical features and ADA2 variants in 33 DADA2 patients. A comparison was made of the transcriptomic profiles from 14 of these patients through bulk RNA sequencing. Additionally, experimental analysis was conducted on ADA2 variants to assess their effects on protein production, trafficking, release, and enzymatic function.
The transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from DADA2 patients with vasculitis or pure red cell aplasia showed similar upregulation of signaling pathways related to TNF, type I interferon, and type II interferon compared to healthy controls. Interestingly, these pathways were also activated in three asymptomatic individuals with DADA2. An analysis of ADA2 variants, including seven novel ones, demonstrated different mechanisms of functional disruption, including unstable transcripts leading to RNA degradation, impairment of ADA2 secretion due to retention in the endoplasmic reticulum, normal expression and secretion of ADA2 lacking enzymatic function, and disruption of the N-terminal signal peptide, causing cytoplasmic localization of unglycosylated protein.
Transcriptomic patterns of inflammation were observed in patients with different disease phenotypes, including some who were asymptomatic. The ADA2 variants linked to the disease affect protein function through multiple mechanisms, potentially contributing to the clinical diversity of DADA2.