Dataset Information

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

ABSTRACT:

Background

Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable.

Objective

We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation.

Methods

Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum.

Results

We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function.

Conclusions

Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

SUBMITTER: Lee PY

PROVIDER: S-EPMC7282972 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

Lee Pui Y PY Kellner Erinn S ES Huang Yuelong Y Furutani Elissa E Huang Zhengping Z Bainter Wayne W Alosaimi Mohammed F MF Stafstrom Kelsey K Platt Craig D CD Stauber Tali T Raz Somech S Tirosh Irit I Weiss Aaron A Jordan Michael B MB Krupski Christa C Eleftheriou Despina D Brogan Paul P Sobh Ali A Baz Zeina Z Lefranc Gerard G Lefranc Gerard G Irani Carla C Kilic Sara S SS El-Owaidy Rasha R Lokeshwar M R MR Pimpale Pallavi P Khubchandani Raju R Chambers Eugene P EP Chou Janet J Geha Raif S RS Nigrovic Peter A PA Zhou Qing Q

The Journal of allergy and clinical immunology 20200113 6

<h4>Background</h4>Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable.<h4>Objective</h4>We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation.<h4>Methods</h4>Patients with DADA2 with severe hematologic manifestations wer ...[more]

PMID: 31945408

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Project description:Several lines of evidence suggest that altered adenosine deaminase (ADA) activity, especially its ADA2 iso-enzyme, is associated with malignant breast cancer (BC) development. Triple-negative breast cancer (TNBC) is currently the most challenging BC subtype due to its metastatic potential and recurrence. Herein, we analyzed the sources of ADA iso-enzymes in TNBC by investigating the effects of cell-to-cell interactions between TNBC cells, macrophages, lymphocytes, and endothelial cells. We also examined the potential relationship between ADA activity and cancer progression in TNBC patients. In vitro analyses demonstrated that the interactions of immune and endothelial cells with MDA-MB-231 triple negative BC cells modulated their extracellular adenosine metabolism pattern. However, they caused an increase in the ADA1 activity, and did not alter ADA2 activity in cancer cells. In turn, the co-culture of MDA-MB-231 cells with THP-1 monocyte/macrophages, Jurkat cells, and human lung microvascular endothelial cells (HULEC) caused the increase in ADA2 activity on THP-1 cells and ADA1 activity on Jurkat cells and HULEC. Clinical sample analysis revealed that TNBC patients had higher plasma ADA2 activities and lower ADA1/ADA2 ratio at advanced stages of cancer development than in the initial stages, while patients with hormone receptor positive, HER2 negative (HR+HER2-), and triple positive (HR+HER2+) breast cancers at the same stages showed opposite trends. TNBC patients also demonstrated positive associations between plasma ADA2 activity and pro-tumor M2 macrophage markers, as well as between ADA1 activity and endothelial dysfunction or inflammatory parameters. The analysis of TNBC patients, at 6 and 12 months following cancer treatment, did not showed significant changes in plasma ADA activities and macrophage polarization markers, which may be the cause of their therapeutic failure. We conclude that alterations in both ADA iso-enzymes can play a role in breast cancer development and progression by the modulation of extracellular adenosine-dependent pathways. Additionally, the changes in ADA2 activity that may contribute to the differentiation of macrophages into unfavorable pro-tumor M2 phenotype deserve special attention in TNBC.

Dataset Information

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

Background

Objective

Methods

Results

Conclusions

Publications

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

Similar Datasets

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