Journal articles: 'Dada2'

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Muratoglu, Selen, Sofia Georgieva, Gábor Pápai, Elisabeth Scheer, Izzet Enünlü, Orbán Komonyi, Imre Cserpán, et al. "Two Different Drosophila ADA2 Homologues Are Present in Distinct GCN5 Histone Acetyltransferase-Containing Complexes." Molecular and Cellular Biology 23, no. 1 (January 1, 2003): 306–21. http://dx.doi.org/10.1128/mcb.23.1.306-321.2003.

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ABSTRACT We have isolated a novel Drosophila (d) gene coding for two distinct proteins via alternative splicing: a homologue of the yeast adaptor protein ADA2, dADA2a, and a subunit of RNA polymerase II (Pol II), dRPB4. Moreover, we have identified another gene in the Drosophila genome encoding a second ADA2 homologue (dADA2b). The two dADA2 homologues, as well as many putative ADA2 homologues from different species, all contain, in addition to the ZZ and SANT domains, several evolutionarily conserved domains. The dada2a/rpb4 and dada2b genes are differentially expressed at various stages of Drosophila development. Both dADA2a and dADA2b interacted with the GCN5 histone acetyltransferase (HAT) in a yeast two-hybrid assay, and dADA2b, but not dADA2a, also interacted with Drosophila ADA3. Both dADA2s further potentiate transcriptional activation in insect and mammalian cells. Antibodies raised either against dADA2a or dADA2b both immunoprecipitated GCN5 as well as several Drosophila TATA binding protein-associated factors (TAFs). Moreover, following glycerol gradient sedimentation or chromatographic purification combined with gel filtration of Drosophila nuclear extracts, dADA2a and dGCN5 were detected in fractions with an apparent molecular mass of about 0.8 MDa whereas dADA2b was found in fractions corresponding to masses of at least 2 MDa, together with GCN5 and several Drosophila TAFs. Furthermore, in vivo the two dADA2 proteins showed different localizations on polytene X chromosomes. These results, taken together, suggest that the two Drosophila ADA2 homologues are present in distinct GCN5-containing HAT complexes.

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Kozlova, A. L., Z. A. Nesterenko, K. K. Egorova, N. Yu Kan, A. L. Khoreva, A. A. Moiseeva, V. I. Burlakov, et al. "THE MANY FACES OF AUTOINFLAMMATION: ADENOSINE DEAMINASE 2 (DADA2) DEFICIENCY IN A 12 YEAR OLD." Pediatria. Journal named after G.N. Speransky 100, no. 2 (April 12, 2021): 246–53. http://dx.doi.org/10.24110/0031-403x-2021-100-2-246-253.

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This article is dedicated to one of the auto-respiratory syndromes – adenosine deaminase deficiency 2 (deficiency of adenosine deaminase 2 – DADA2) in the 12-year-old. This rare disease is caused by mutations in the ADA2 gene (CECR1), that encodes the ADA2 protein. Clinical manifestations of DADA2 are very diverse and usually include systemic inflammatory reaction in the form of fever attacts, vasculopathy in the form of livedo reticulum, polyarteritis nodosa, ischemic and/or hemorrhagic strokes, as well as signs of immunodeficiency with hypogammaglobulinemia and bone marrow failure. Complex pathogenetic mechanisms, variety of clinical manifestations complicate both diagnosis of the disease and trial of pathogenetic therapy in patients with DADA2. The article describes DADA2 patient care, as well as provides present state analysis of the DADA2 problem in the world, including terminology, historical references, pathogenesis, diagnosis problems and clinical manifestations.

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Alabbas, Fahad, Ghaleb Elyamany, Omar Alsharif, Michael Hershfield, and Isabelle Meyts. "Childhood Hodgkin Lymphoma: Think DADA2." Journal of Clinical Immunology 39, no. 1 (January 2019): 26–29. http://dx.doi.org/10.1007/s10875-019-0590-7.

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Collison, Joanna. "Stem cell transplantation for DADA2." Nature Reviews Rheumatology 13, no. 12 (October 20, 2017): 694. http://dx.doi.org/10.1038/nrrheum.2017.175.

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Özen, Seza, Ezgi Deniz Batu, Ekim Z. Taşkıran, Hatice Asuman Özkara, Şule Ünal, Naz Güleray, Abdulsamet Erden, et al. "A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2." Journal of Rheumatology 47, no. 1 (May 1, 2019): 117–25. http://dx.doi.org/10.3899/jrheum.181384.

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Objective.Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients.Methods.This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method.Results.Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients.Conclusion.We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype–phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.

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Kaya Akca, U., E. Sag, Ş. Ünal, M. Kasap-Cuceoglu, Y. Bilginer, and S. Özen. "OP0168 THE ROLE OF VASCULAR INFLAMMATION MARKERS IN DEFICIENCY OF ADENOSINE DEAMINASE 2." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 100.1–101. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2504.

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Background:Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease whose pathogenesis has not been clearly elucidated.Objectives:To investigate the role of vascular inflammatory factors in the pathogenesis of DADA2, to compare the vascular inflammation profiles of DADA2 patients with different phenotypes, and to compare DADA2 patients with classic polyarteritis nodosa (PAN).Methods:The study included eighteen DADA2 patients, ten PAN patients, and eight healthy controls. Plasma levels of sST2, sRAGE, Tie-2, sCD40L, Tie-1, sFlt-1, LIGHT, TNF-α, PlGF, IL-6, IL-18, IL-10, MCP-1 were studied by cytometric bead-based multiplex assay panel.Results:Among the DADA2 patients, five had hematological manifestations, 13 had vasculitic findings, and accompanying immunological findings were present in seven patients. Nine patients had neurological findings, five of whom had neuropathy. Hematological findings were Diamond-Blackfan anemia-like phenotype in four patients and bicytopenia (anemia and thrombocytopenia) in one patient. Disease characteristics of DADA2 and PAN patients revealed that neurological involvement and livedo reticularis were more frequent in DADA2 patients (p=0.034 and p=0.009, respectively), while myalgia was more common in PAN patients (p:0.001).Plasma levels of Tie-1 and sFlt-1 were higher in the overall DADA2 patients compared to healthy controls and PAN patients (p<0.001 and p=0.004, respectively). DADA2 patients with PAN-like features had higher sRAGE, Tie-2, and TNF-α levels compared to PAN patients (p=0.013, p=0.003, and p=0.001, respectively).There was no significant difference in the levels of vascular inflammation markers between DADA2 patients with vasculitis and hematological involvement except IL-18. The plasma IL-18 levels were higher in the DADA2 patients with hematological findings compared to vasculitic phenotype (p=0.001). Finally DADA2 patients with neuropathy had higher sRAGE concentrations than patients without neuropathy and healthy controls (p=0.03 and p=0.008, respectively).Conclusion:We suggest that the high plasma IL-18 levels may be associated with an activated IFN pathway, the pathogenesis of hematologic manifestations, and unresponsive to anti-TNF treatment. Higher concentrations of Tie-1, Tie-2, sFlt-1, sRAGE, and TNF-α distinguished DADA2 patients with PAN-like features from PAN patients. We identified sRAGE as a potential biomarker of neuropathy in DADA2 patients.References:[1]Pesciotta EN, Lam H-S, Kossenkov A, et al. In-Depth, Label-Free analysis of the erythrocyte cytoplasmic proteome in Diamond Blackfan Anemia identifies a unique inflammatory signature. PLoS One 2015;10(10):e0140036.[2]Haslbeck KM, Bierhaus A, Erwin S, et al. Receptor for advanced glycation endproduct (RAGE)–mediated nuclear factor-κB activation in vasculitic neuropathy. Muscle Nerve 2004;29(6):853-60.Disclosure of Interests:None declared

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Arts, Katrijn, Jenna R. E. Bergerson, Amanda K. Ombrello, Morgan Similuk, Andrew J. Oler, Anahita Agharahimi, Emily M. Mace, et al. "Warts and DADA2: a Mere Coincidence?" Journal of Clinical Immunology 38, no. 8 (November 2018): 836–43. http://dx.doi.org/10.1007/s10875-018-0565-0.

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Watanabe, Naoki, Shouguo Gao, Sachiko Kajigaya, Carrie Diamond, Lemlem Alemu, Amanda Ombrello, and Neal S. Young. "Analysis of Deficiency of Adenosine Deaminase 2 Pathogenesis Based on Single Cell RNA Sequencing of Monocytes." Blood 134, Supplement_1 (November 13, 2019): 2317. http://dx.doi.org/10.1182/blood-2019-123859.

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Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disease caused by loss-of-function mutations in the ADA2 gene. DADA2 typically presents in childhood and is characterized by vasculopathy, stroke, inflammation, and immunodeficiency as well as hematologic manifestations, such as bone marrow failure and lymphoproliferation. The ADA2 protein is predominantly expressed in stimulated monocytes, dendritic cells and macrophages. ADA2 increases in the setting of inflammation and/or infection conditions. ADA2 has been reported to have a critical role in maintaining the balance between M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. Macrophages of DADA2 patients are polarized towards M1 subset., DADA2 pathogenesis is not well characterized. To elucidate molecular mechanisms in DADA2 deficiency, we analyzed a gene expression profile of CD14+ monocytes derived from peripheral blood using single cell RNA sequencing (scRNA-seq). Blood was collected from DADA2 patients and age- and sex-matched healthy donors; all patients were studied in a registered research protocol (clinicaltrials.gov NCT00071045). Samples were obtained from 14 DADA2 patients and 6 healthy donors; median age of the DADA2 patients was 23 years old (range, 5 - 57 years). Among the 14 patients, 7 had hematological phenotypes: 5 lymphopenia, 3 neutropenia, 3 thrombocytopenia, and 2 with hypocellular bone marrow histology. Low serum immunoglobulins and cutaneous findings were frequent. Nine of the 14 patients had been treated with TNF inhibitors (etanercept and adalimumab). Mutations were distributed throughout the ADA2 gene; although two siblings had the same mutation, even they showed poor genotype-phenotype correlation. Monocytes were isolated by immunomagnetic positive selection with the EasySep™ positive CD14 selection kit Ⅱ, then subjected to scRNA-seq using Single Cell 3' Reagent Kits v2 (10X Genomics). Libraries for scRNA-seq were sequenced on the HiSeq-3000 instrument. Based on scRNA-seq data, we could classify monocytes into three populations by conventional flow cytometric criteria using cell surface protein expression imputed from scRNA-seq: CD14++CD16- classical, CD14++CD16+ intermediate, and CD14+CD16++ nonclassical monocytes (Figure A). CD16 expression was higher in DADA2 patients than in healthy donors (Figure B). A proportion of nonclassical monocytes among total monocytes were significantly higher in DADA2 patients compared to healthy donors (Figure C). On comparison of gene expression of each monocyte subtypes in DADA2 patients with that of healthy donors, there were 215, 237, and 267 differentially expressed upregulated genes in classical, intermediate, and nonclassical monocytes, respectively (at a threshold avg_logFC > 0.2). Approximately 35% of upregulated genes were overlapped among the three monocyte subtypes of DADA2 patients, including immune response genes such as IFITM1, IFITM2, IFITM3, and C3AR1 (Figure D). Common gene pathways were associated with immune function, such as interferon alpha/beta signaling and interferon gamma signaling. Specific genes to classical and intermediate monocytes were less than 10% of all the upregulated genes. Distinctively, the NF-κB pathway was upregulated in nonclassical monocytes, this might contribute to the pathogenesis of DADA2 as inflammatory disease. Overall, each monocyte subtype of DADA2 patients showed upregulation of immune response gene sets compared to controls. DADA2 patients have increased numbers of nonclassical monocytes which may contribute the immune dysregulation and increased inflammation observed in the disease. Figure Disclosures No relevant conflicts of interest to declare.

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Carmona-Rivera, Carmelo, Sami S. Khaznadar, Kyawt W. Shwin, Jorge A. Irizarry-Caro, Liam J. O’Neil, Yudong Liu, Kenneth A. Jacobson, et al. "Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2." Blood 134, no. 4 (July 25, 2019): 395–406. http://dx.doi.org/10.1182/blood.2018892752.

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Abstract Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vasculitis, at least in part, through the formation of neutrophil extracellular traps (NETs). The study objective was to determine whether neutrophils and NETs play a pathogenic role in DADA2. In vivo evidence demonstrated NETs and macrophages in affected gastrointestinal tissue from patients with DADA2. An abundance of circulating LDGs prone to spontaneous NET formation was observed during active disease in DADA2 and were significantly reduced after remission induction by anti–tumor necrosis factor (TNF) therapy. Increased circulating LDGs were identified in unaffected family members with monoallelic ADA2 mutations. Adenosine triggered NET formation, particularly in neutrophils from female patients, by engaging A1 and A3 adenosine receptors (ARs) and through reactive oxygen species– and peptidylarginine deiminase–dependent pathways. Adenosine-induced NET formation was inhibited by recombinant ADA2, A1/A3 AR antagonists, or by an A2A agonist. M1 macrophages incubated with NETs derived from patients with DADA2 released significantly greater amounts of TNF-α. Treatment with an A2AAR agonist decreased nuclear translocation of NF-κB and subsequent production of inflammatory cytokines in DADA2 monocyte-derived macrophages. These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases.

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Lee, Pui Y. "NETing the mechanism of inflammation in DADA2." Blood 134, no. 4 (July 25, 2019): 338–39. http://dx.doi.org/10.1182/blood.2019001251.

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Yap, Jin Yan, Leen Moens, Ming-Wei Lin, Alisa Kane, Anthony Kelleher, Catherine Toong, Kathy H. C. Wu, et al. "Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency." Journal of Clinical Immunology 41, no. 8 (October 17, 2021): 1915–35. http://dx.doi.org/10.1007/s10875-021-01141-0.

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Abstract Purpose Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. Methods In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. Results The median age of the patients was 10 years (mean 20.7 years, range 1–44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. Conclusion Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.

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Hashem, Hasan, Ashish R. Kumar, Ingo Müller, Florian Babor, Robbert Bredius, Jignesh Dalal, Amy P. Hsu, et al. "Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2." Blood 130, no. 24 (December 14, 2017): 2682–88. http://dx.doi.org/10.1182/blood-2017-07-798660.

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Key Points HSCT represents an effective and definitive treatment of DADA2. HSCT can cure the immunological, hematological, and vascular phenotype of DADA2 with 100% survival at median follow-up of 18 months.

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Wang, W., T. Zhang, L. Wang, and H. Song. "FRI0472 DIAGNOSIS AND MANAGEMENT OF ADENOSINE DEAMINASE 2 DEFICIENCY CHILDREN: THE EXPERIENCE FROM CHINA." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 833.1–833. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3481.

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Background:Adenosine deaminase 2 deficiency (DADA2) is a rare antoinflammatory disease caused by mutations in ADA2 gene, few Chinese cases have been reported.Objectives:To describe and compare the clinical features, genotypes, and treatments of Chinese DADA2 patients and foreign cases.Methods:Primary immunodeficiency disease Panel or Whole Exome Sequencing was performed to suspected subjects, and assays for adenosine deaminase 2(ADA2) enzyme activity were also carried out to them and their parents. Case reports of Chinese and foreign patients with DADA2 were searched from PubMed and Chinese domestic databases.Results:Seven unrelated DADA2 children from China were included in our study, 5 were identified at Peking union medical college hospital and 2 had been reported previously (1 on PubMed and 1 in Chinese literatures). 14 mutations in ADA2 were identified, and 9 of which have not been found in other countries. Four children receiving enzymatic analysis had lower ADA2 enzyme activity compared to their parents. Phenotypic manifestations included fever, skin symptoms, vasculitis, neurologic involvement, et al. The treatments varying from steroids, immunosuppressants, and tocilizumab, anti-TNF therapy and hematopoietic stem cell transplantation (HSCT) were effective depending on different phenotype and severity.Conclusion:This study includes the biggest number of Chinese DADA2 patients at present. We recommend combination of enzymatic analysis with gene screening to confirm the diagnosis. Genotypes of patients from China were some different, the clinical manifestations were similar. We suggest anti-TNF therapy may not be necessary for mild case and HSCT should be considered even without hematological phenotype.References:[1]Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370:911-920.[2]Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. J Clin Immunol. 2018;38:569-578.[3]Wang XN, Zhou ZX, Li SN, Lai JM, Su GX, Kang M, et al. A case report of DADA2. Chin J Rheumatol. 2019;23:476-478.[4]Liu L, Wang W, Wang Y, Hou J, Ying W, Hui X, et al. A Chinese DADA2 patient: report of two novel mutations and successful HSCT. Immunogenetics. 2019;71:299-305.Disclosure of Interests:None declared

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Santo, Gustavo C., Inês Baldeiras, Rita Guerreiro, Joana A. Ribeiro, Rosário Cunha, Taryn Youngstein, Sira Nanthapisal, et al. "Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon’s Syndrome of Unknown Cause." Cerebrovascular Diseases 46, no. 5-6 (2018): 257–64. http://dx.doi.org/10.1159/000495794.

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Background: The association that exists between livedo reticularis (LR) and stroke is known as Sneddon’s syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC). Methods: ADA2 activity in plasma and serum IgM concentrations was measured in adult patients within the SnS spectrum, healthy first-degree relatives and HC. Genetic results were used as the reference standard. The primary outcome measures were sensitivity and specificity derived from receiver operating curve analysis. Results: A total of 73 participants were included in the study: 26 patients with PSnS with no CECR1 mutation (PSnS), 6 bi-allelic (DADA2 patients) and 7 HHZ CECR1 mutations and 34 HC. Plasma ADA2 activity and serum IgM levels were significantly lower in DADA2 patients than in PSnS. With the use of the best indexes, plasma ADA2 activity differentiated PSnS from DADA2 with a sensitivity and specificity of 100.0% and HHZ from HC with a sensitivity of 97.1% and specificity of 85.7%. Serum IgM levels also differentiated PSnS from DADA2 with a sensitivity of 85.2% and specificity of 83.3%. Conclusion: Serum IgM levels might be used as a triage tool and plasma ADA2 activity performs perfectly as a diagnostic test for DADA2 in adult patients within the SnS spectrum. ADA2 activity in plasma also reliably distinguishes HHZ from HC.

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Lee, Seo-Young, Yeuni Yu, Jin Chung, and Hee Sam Na. "Trimming conditions for DADA2 analysis in QIIME2 platform." International Journal of Oral Biology 46, no. 3 (September 30, 2021): 146–53. http://dx.doi.org/10.11620/ijob.2021.46.3.146.

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Barnes, Christopher J., Linett Rasmussen, Maria Asplund, Steen Wilhelm Knudsen, Maja-Lisa Clausen, Tove Agner, and Anders J. Hansen. "Comparing DADA2 and OTU clustering approaches in studying the bacterial communities of atopic dermatitis." Journal of Medical Microbiology 69, no. 11 (November 1, 2020): 1293–302. http://dx.doi.org/10.1099/jmm.0.001256.

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Introduction. The pathogenesis of atopic dermatitis (AD) is not yet fully understood, but the bacterial composition of AD patients’ skin has been shown to have an increased abundance of Staphylococcus aureus . More recently, coagulase-negative Staphylococcus (CoNS) species were shown to be able to inhibit S. aureus , but further studies are required to determine the effects of Staphylococcus community variation in AD. Aim. Here we investigated whether analysing metabarcoding data with the more recently developed DADA2 approach improves metabarcoding analyses compared to the previously used operational taxonomic unit (OTU) clustering, and can be used to study Staphylococcus community dynamics. Methods. The bacterial 16S rRNA region from tape strip samples of the stratum corneum of AD patients (non-lesional skin) and non-AD controls was metabarcoded. We processed metabarcoding data with two different bioinformatic pipelines (an OTU clustering method and DADA2), which were analysed with and without technical replication (sampling strategy). Results. We found that OTU clustering and DADA2 performed well for community-level studies, as demonstrated by the identification of significant differences in the skin bacterial communities associated with AD. However, the OTU clustering approach inflated bacterial richness, which was worsened by not having technical replication. Data processed with DADA2 likely handled sequencing errors more effectively and thereby did not inflate molecular richness. Conclusion. We believe that DADA2 represents an improvement over an OTU clustering approach, and that biological replication rather than technical replication is a more effective use of resources. However, neither OTU clustering nor DADA2 gave insights into Staphylococcus community dynamics, and caution should remain in not overinterpreting the taxonomic assignments at lower taxonomic ranks.

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Alabbas, Fahad, Omar Alsharief, Isabelle Meyts, Fatma Albatniji, Michael Hershfield, Adnan Mansoor, and Ghaleb Elyamany. "Deficiency of Adenosine Deaminase 2 (DADA2) Presenting As Familial Hodgkin Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 5373. http://dx.doi.org/10.1182/blood-2018-99-116431.

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Abstract Familial Hodgkin Lymphoma (HL) accounts for 4.5% of HL. Both genetic susceptibility and shared environmental factors can play a role. The usual presentation of HL is cervical lymphadenopathy/ mediastinal mass. Subdiaphragmatic presentation is rare and hepatosplenomegaly is associated with advanced HL. Adenosine deaminase 2 (ADA2) act as an outside extracellular growth factor for integrity of endothelial cells and in the development of certain immune cells. Deficiency of ADA2 (DADA2) is a recently described inborn error of immunity caused by biallelic mutations in adenosine deaminase 2 (ADA2) gene (formerly known as CECR1). It is an auto-inflammatory disorder with a spectrum of vascular, inflammatory, hematological and immunodeficiency phenotypes. The condition is inherited in an autosomal recessive pattern.The association of DADA2 with lymphoproliferation such asT-LGL like condition and ALPS like disease have been reported, however, HL has not previously been reported in DADA2. Herein we describe two siblings with DADA2 who presented with Hodgkin Lymphoma. The first patient is the third child of Saudi first degree related parents. He is known to have bronchial asthma on bronchodilators. At the age of 5 years, he was referred from primary care clinic for investigation of hepatosplenomegaly. He was otherwise well with growth along the fifth centile. His complete blood count (CBC) showed mild lymphopenia, other lab results including liver function tests were within normal. Few months later, he developed non-tender mobile cervical lymph nodes enlargement. Viral serology including EBV was negative based on PCR testing. Lymph node biopsy revealed the diagnosis of HL, mixed cellularity type, EBV negative (Figure 1). Whole exome analysis sequencing identified a homozygous variant in ADA2 gene c.1447_1451del. This variant has been confirmed by Sanger sequencing. Plasma assay of ADA2 enzyme activity revealed undetectable levels compatible with ADA2 deficiency. The patient started on prednisone 2 mg/kg/day, which showed good response in the form of being off blood support and regression of splenomegaly. Few months later, the course was complicated by recurrent infections. The patient remained stable for three years on small dose of prednisone, monthly IVIG due to hypogammaglobulinemia. Recently, etanercept was started to control disease progression. Nine months after the diagnosis of first patient, his younger brother who is known to have mild bronchial asthma on bronchodilators presented at the age of five years with hepatosplenomegaly and generalized lymphadenopathy. Lymph node biopsy revealed the diagnosis of classical HL, lymphocyte-rich subtype. Similar to his sibling, whole exome analysis identified the same mutation (a homozygous variant in ADA2 gene c.1447_1451del). This variant has been confirmed by Sanger sequencing and plasma level of ADA2 enzyme activity was undetectable. After the diagnosis of DADA2, screening for serum immunoglobulin levels showed hypogammaglobulinemia. The patient continues to be off treatment. Both patients were treated with chemotherapy with or without radiotherapy showing good response and they remained in remission at respectively and months after cessation of chemotherapy. This study is important for several reasons. First, this is the first report of HL in the context of DADA2. This again widens the clinical spectrum of DADA2. Interestingly, the boys presented two different forms of HL at the cellular level with no evidence of viral infection. The reported siblings presented with subdiaphragmatic diseases, which is uncommon in HL but in line with the sites of lymphoproliferation in DADA2. In addition, the age of presentation in the two siblings is uncommon in HL (less than 10 years). Second, we report an novel mutation in ADA2 gene. It creates a shift in the reading frame starting at codon Ser483. The new reading frame ends in a stop codon 4 positions downstream. This description and the description of the HL occurrence further expands the spectrum of DADA2. Our data, call for judicious exclusion of ADA2 deficiency in the HL patient with an aberrant course and additional symptoms / signs. In summary, we report familial HL in two patients with a novel deleterious mutation in ADA2 gene. This expands the spectrum of this disease to include cancer and should alert the hemato-oncologist to the possibility of DADA2 as an underlying diagnosis in HL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Schwartz, Daniella Muallem, Moses M. Kitakule, Brian LP Dizon, Cristhian Gutierrez-Huerta, Sarah A. Blackstone, Aarohan M. Burma, Aran Son, et al. "Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features." Annals of the Rheumatic Diseases 80, no. 6 (February 22, 2021): 788–95. http://dx.doi.org/10.1136/annrheumdis-2020-219137.

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Background Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown. Objectives We investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy). Methods In this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed. Results Clinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20. Conclusions CAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.

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Kasap Cuceoglu, Muserref, Seher Sener, Ezgi Deniz Batu, Ummusen Kaya Akca, Selcan Demir, Erdal Sag, Erdal Atalay, et al. "Systematic review of childhood-onset polyarteritis nodosa and DADA2." Seminars in Arthritis and Rheumatism 51, no. 3 (June 2021): 559–64. http://dx.doi.org/10.1016/j.semarthrit.2021.04.009.

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Callahan, Benjamin J., Paul J. McMurdie, Michael J. Rosen, Andrew W. Han, Amy Jo A. Johnson, and Susan P. Holmes. "DADA2: High-resolution sample inference from Illumina amplicon data." Nature Methods 13, no. 7 (May 23, 2016): 581–83. http://dx.doi.org/10.1038/nmeth.3869.

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Michniacki, Thomas F., Mark Hannibal, Charles W. Ross, David G. Frame, Adam S. DuVall, Rami Khoriaty, Mark T. Vander Lugt, and Kelly J. Walkovich. "Hematologic Manifestations of Deficiency of Adenosine Deaminase 2 (DADA2) and Response to Tumor Necrosis Factor Inhibition in DADA2-Associated Bone Marrow Failure." Journal of Clinical Immunology 38, no. 2 (February 2018): 166–73. http://dx.doi.org/10.1007/s10875-018-0480-4.

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Zoccolillo, Matteo, Immacolata Brigida, Federica Barzaghi, Serena Scala, Raisa Jofra Hernández, Luca Basso-Ricci, Mariasilvia Colantuoni, et al. "Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency." Blood Advances 5, no. 16 (August 20, 2021): 3174–87. http://dx.doi.org/10.1182/bloodadvances.2020003811.

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Abstract Adenosine deaminase 2 deficiency (DADA2) is a rare inherited disorder that is caused by autosomal recessive mutations in the ADA2 gene. Clinical manifestations include early-onset lacunar strokes, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic defects. Anti–tumor necrosis factor therapy reduces strokes and systemic inflammation. Allogeneic hematopoietic stem/progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for complications. Autologous HSPC gene therapy may be an alternative curative option for patients with DADA2. We designed a lentiviral vector encoding ADA2 (LV-ADA2) to genetically correct HSPCs. Lentiviral transduction allowed efficient delivery of the functional ADA2 enzyme into HSPCs from healthy donors. Supranormal ADA2 expression in human and mouse HSPCs did not affect their multipotency and engraftment potential in vivo. The LV-ADA2 induced stable ADA2 expression and corrected the enzymatic defect in HSPCs derived from DADA2 patients. Patients’ HSPCs re-expressing ADA2 retained their potential to differentiate into erythroid and myeloid cells. Delivery of ADA2 enzymatic activity in patients’ macrophages led to a complete rescue of the exaggerated inflammatory cytokine production. Our data indicate that HSPCs ectopically expressing ADA2 retain their multipotent differentiation ability, leading to functional correction of macrophage defects. Altogether, these findings support the implementation of HSPC gene therapy for DADA2.

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Pardinhas, Clara, Gustavo Santo, Luís Escada, Jorge Rodrigues, Maria Rosário Almeida, Rui Alves, and Manuel Salgado. "A Case of Deficiency of Adenosine Deaminase 2: 28 years of Diagnostic Challenges." Case Reports in Nephrology and Dialysis 11, no. 3 (November 18, 2021): 340–47. http://dx.doi.org/10.1159/000517141.

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Deficiency of adenosine deaminase 2 (DADA2) is a unique monogenic autoinflammatory disease caused by autosomal recessive loss-of-function mutations in the CECR1 gene which presents as childhood-onset small- and medium-vessel vasculitis. Previously, many of these patients were misdiagnosed and thought to have clinical features of systemic polyarteritis nodosum, which negatively influenced its outcome, since TNF inhibitors seem to have efficacy on the vasculitic phenotype of DADA2. We present a case of a 28-year-old woman with a lifelong unknown syndrome and unique clinical manifestations recently recognized as DADA2. The first manifestation, at 3 months of age, was an episode of facial paralysis during which renovascular hypertension was diagnosed. Later, she developed episodes of prolonged fever, polyarthritis, Raynaud’s phenomenon, gastrointestinal bleeding, and intracerebral hemorrhage. This inflammatory state ultimately led to the development of amyloid A amyloidosis and renal insufficiency.

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Vai, Silvia, Erika Marin, Roberta Cosso, Francesco Saettini, Sonia Bonanomi, Alessandro Cattoni, Iacopo Chiodini, Luca Persani, and Alberto Falchetti. "A Novel Germline Mutation of ADA2 Gene in Two “Discordant” Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype." International Journal of Molecular Sciences 22, no. 15 (August 3, 2021): 8331. http://dx.doi.org/10.3390/ijms22158331.

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Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up.

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Cafaro, Alessia, Federica Pigliasco, Sebastiano Barco, Federica Penco, Francesca Schena, Roberta Caorsi, Stefano Volpi, Gino Tripodi, Marco Gattorno, and Giuliana Cangemi. "A Novel LC–MS/MS-Based Method for the Diagnosis of ADA2 Deficiency from Dried Plasma Spot." Molecules 26, no. 18 (September 21, 2021): 5707. http://dx.doi.org/10.3390/molecules26185707.

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Adenosine Deaminase 2 Deficiency (DADA2) (OMIM: 607575) is a monogenic, autoinflammatory disease caused by the loss of functional homozygous or heterozygous mutations in the ADA 2 gene (previously CECR1, Cat Eye Syndrome Chromosome Region 1). A timely diagnosis is crucial to start Anti-TNF therapies that are efficacious in controlling the disease. The confirmation of DADA2 is based on DNA sequencing and enzymatic assay. It is, thus, very important to have robust and reliable assays that can be rapidly utilized in specialized laboratories that can centralize samples from other centers. In this paper, we show a novel enzymatic assay based on liquid chromatography-tandem mass spectrometry that allows the accurate determination of the ADA2 enzyme activity starting from very small amounts of plasma spotted on filter paper (dried plasma spot). The method allows significantly distinguishing healthy controls from affected patients and carriers and could be of help in implementing the diagnostic workflow of DADA2.

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Szvetnik, Enikoe Amina, Christian Klemann, Ina Hainmann, Marie-Francoise O'-Donohue, Tamás Farkas, Marena Niewisch, Regine Grosse, et al. "Diamond-Blackfan Anemia Phenotype Caused By Deficiency of Adenosine Deaminase 2." Blood 130, Suppl_1 (December 7, 2017): 874. http://dx.doi.org/10.1182/blood.v130.suppl_1.874.874.

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Abstract Diamond-Blackfan anemia (DBA) is a prototypic ribosomopathy and remains the most common cause of congenital pure red cell aplasia (PRCA). In 2/3 of patients, ribosomal protein haploinsufficiency is disease-causing, while in remaining 1/3 the genetic etiology is unknown. Recently, deficiency of ADA2 (DADA2) due to biallelic CECR1 -mutations was reported in patients with systemic autoinflammatory disease presenting with early onset vasculopathy, strokes, antibody deficiency, and in some cases variable cytopenias. Based on the clinical findings in an ADA2-deficient patient with PRCA resembling DBA, we aimed to define the prevalence and clinical picture of DADA2 within DBA patient cohorts. Patients enrolled in the national observational DBA registry in Germany were evaluated for the presence of mutations in CECR1 gene; additional nonconsecutive patients from the French and Turkish registries within the European DBA (EuroDBA) consortium were part of this study. Functional studies included profiling of polysomes and pre-rRNAs in patient-derived EBV-cell lines, CECR1 RT-PCR, measurements of autophagy and apoptosis, and analysis of erythropoiesis in zebrafish embryos. Systematic mutational and copy number analysis had identified typical ribosomal haploinsufficiency in 169/242 patients (70%). Out of 73 remaining patients, full CECR1 -sequencing was accomplished in 68 cases, of which 4 (6%) carried biallelic CECR1 -mutations. Additional 3 patients with biallelic CECR1 -mutations and DBA phenotype were referred from Germany (the index PRCA case), France and Turkey. In contrast to typical autoinflammatory DADA2 (caused by missense biallelic CECR1 -mutations) all patients studied here had at least one CECR1 -allele affected by truncating/stop-gain/deletion mutation leading to mRNA degradation in patient cells. Low or missing ADA2 enzyme activity in plasma confirmed DADA2, while erythrocyte ADA (eADA) levels and MCV were normal. Transfusion-dependent hypoproliferative anemia developed at a median age of 5 weeks (birth-14 years), while hypogammaglobulinemia developed in all cases either initially or during disease course. Notably, a transient hematologic response to steroids was achieved in 5/7 patients, but no improvement was observed in 2 patients treated with TNF-inhibitor; all patients at one point became heavily transfusion-dependent. Systemic vasculitis or cerebral complications were not observed in our cohort. At the last follow-up, 6/7 patients were alive; 3 had successfully undergone hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning and 1 patient had died due to septic shock. Next, we addressed the question if ribosome biogenesis is affected in ADA2-deficient patient cells. Using pre-rRNA maturation assays, polysome profiling and Western blots we established that ribosome biogenesis is normal in DADA2-related PRCA and there is no increase of TP53 stabilization over basal levels in patient LCLs. Analysis of CECR1 -morpholino zebrafish embryos revealed early anemia with lethal phenotype. Although there was no evidence for extrinsic (e.g. immune-mediated) pathomechanisms in our patients, it remains to be answered if CECR1 loss directly affects erythroid development. Finally, the association between elevated levels of eADA (=ADA1) specific to classical DBA and decreased ADA2 enzyme levels in DADA2-related PRCA remains obscure. In summary, DADA2 can phenotypically mimic DBA and thus extends the spectrum of congenital PRCA. Ribosome synthesis seems not to be affected by CECR1 mutations. DADA2 should be considered in patients with DBA-like phenotype but with normal eADA/MCV and hypogammaglobulinemia, allowing for early stratification aimed at HSCT in affected individuals. Disclosures Grosse: Addmedica: Membership on an entity's Board of Directors or advisory committees.

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Pimpale Chavan, Pallavi, Divya Ramadoss, Archana Khan, Pui Y. Lee, and Raju Khubchandani. "Deficiency of Adenosine Deaminase 2 (DADA2): One Disease, Several Faces." Indian Journal of Pediatrics 88, no. 8 (May 31, 2021): 828–30. http://dx.doi.org/10.1007/s12098-021-03809-2.

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Sönmez, Hafize Emine, Ezgi Deniz Batu, Ekim Z. Taşkıran, Mehmet Alikaşifoğlu, Yelda Bilginer, and Seza Özen. "Genetic testing for DADA2: How can we avoid missing patients?" European Journal of Human Genetics 26, no. 11 (September 11, 2018): 1563–65. http://dx.doi.org/10.1038/s41431-018-0240-1.

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Insalaco, Antonella, Gian Marco Moneta, Manuela Pardeo, Ivan Caiello, Virginia Messia, Claudia Bracaglia, Chiara Passarelli, and Fabrizio De Benedetti. "Variable Clinical Phenotypes and Relation of Interferon Signature with Disease Activity in ADA2 Deficiency." Journal of Rheumatology 46, no. 5 (January 15, 2019): 523–26. http://dx.doi.org/10.3899/jrheum.180045.

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Objective.An upregulation of type I interferon (IFN) stimulated genes [IFN score (IS)] was described in patients with adenosine deaminase 2 deficiency (DADA2). We describe the clinical course of 5 such patients and the role of IS as a marker of disease activity and severity.Methods.Expression levels of IS were determined by quantitative real-time PCR.Results.Five white patients were identified as carrying CECR1 mutations. The IS before treatment was elevated in 4 out of 5 patients and decreased after treatment.Conclusion.Our data confirm the high variability of DADA2 and suggest type I IS as a biomarker of disease activity.

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Mamadapur, M., S. Mahadevan, A. Singh, R. Chakravarthy C H, R. S, and T. T N. "AB0733 DADA2 VASCULITIS PRESENTING AS POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES): AN ATYPICAL PRESENTATION." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1396.3–1397. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2660.

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Background:Deficiency of Adenosine Aminase deficiency 2 is monogenic disease presenting with multisystem involvement of vasculitis,Stroke1,hematological manifestations. We hereby present a young child who presented with PRES initially and later diagnosed as DADA2.Only one case of DADA2 presenting as PRES is reported so far2.This case highlights the atypical presentation of DADA2.Objectives:A case report to highlight the rare presentation of DADA2 vasculits.Methods:8 year old developmentally normal male child,born out of consanguineous marriage presented with with fever,abdominal pain, seizures 1 year back.Ultrasound of abdomen revelaed mesenteric lymphadenitis and MRI Brain was suggestive of Meningoencephalitis.He was managed with antivirals and antibiotics then.6 months later,he had fever,skin rash,pain abdomen,status epilepticus,hypertension followed by gangrene of fingers and toes.APLA,ANA,ANCA workup was negative. Complete Hemogram was normal. CRP was 130mg/dl. CT Abdomen was normal and no evidence of aneurysms. Renal Doppler Ultrasound was normal.CT upper limb showed left radial and ulnar artery significant narrowing with patchy occlusion. MRI Brain showed bilateral fronto parietal,occipital,putamen,left insula and subcortical and cortical T2W FLAIR hyperintensity without diffusion restriction suggestive of PRES. He was diagnosed as Childhood Polyarteritis Nodosa and treated with cyclophosphamide. Genetic Analysis of ADA2(CECR1) gene mutation by Sanger Sequencing of exons 2 to 10 showed a known variant (rs202134424) in ADA2 gene.Figure 1.Gangrene of left 1-5th digits and right 4th and 5th digit resorptionFigure 2.T2W FLAIR image showing bilateral fronto parietal,occipital,putamen,left insula and subcortical and cortical hyperintensity without diffusion restriction suggestive of PRES.Results:He was started on Infliximab and is on follow up. No further events noted so far.Rehabilitation of left upper hand was done.Conclusion:DADA2 can present with varied CNS manifestations like infarct,hemorrhage,aneurysms and PRES.High index of suspicion and early recognition can help in maintaining vascular integrity.References:[1]Ganhão S, Loureiro G, Oliveira D, dos-Reis-Maia R, Aguiar F, Quental R et al. Two cases of ADA2 deficiency presenting as childhood polyarteritis nodosa: novel ADA2 variant, atypical CNS manifestations, and literature review. Clinical Rheumatology. 2020;39(12):3853-3860.[2]Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V et al. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India. Arthritis & Rheumatology. 2020;73(2):276-285.Disclosure of Interests:None declared

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Motto, Cristina, Federica Teutonico, Nicola Tovaglieri, Paola Doneda, Mariangela Piano, Aglaia Vignoli, Costantino De Giacomo, and Elio Clemente Agostoni. "Ischemic stroke as presentation of DADA2: Case report and literature review." Journal of the Neurological Sciences 429 (October 2021): 118886. http://dx.doi.org/10.1016/j.jns.2021.118886.

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Amikishiyev, S., B. Ince, M. Bektas, Y. Yalçinkaya, B. Artim-Esen, M. Inanc, and A. Gül. "AB1300 AA AMYLOIDOSIS IN A PATIENT WITH MUTATIONS IN BOTH ADA2 AND A20 GENES." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1756.2–1757. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3346.

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BackgroundAdenosine Deaminase 2 Deficiency (DADA2) and Haploinsufficiency of A20 (HA20) are two recently described monogenic autoinflammatory diseases (AID). The uncontrolled inflammatory response has been associated with an increased risk of AA amyloidosis in other AID, but there are only two reported patients with DADA2-related amyloidosis so far.1,2ObjectivesWe herein report a patient with AA amyloidosis and AID associated with both DADA2 and HA20.MethodsWe used the Ion Torrent platform for deep sequencing.ResultsCase: A 20-year-old male patient born to consanguineous parents (Figure 1), was admitted to our hospital with fever and abdominal pain in June 2014. Peritonitis, hepatomegaly, and a palpable non-tender mass in the right axillary cavity were detected in physical examination, and his laboratory investigations revealed neutrophilic leukocytosis, high acute phase reactants (APR), and nephrotic range proteinuria. CT angiography showed multiple thrombotic microaneurysms in celiac, splenic, superior, and inferior mesenteric and bilateral renal arteries; and MRI documented an additional aneurysm in anterior communicating artery. No finding was detected in hepatitis serology. He had been diagnosed with polyarteritis nodosa, and prednisolone and azathioprine were started. Renal histopathology confirmed the AA amyloidosis. Genetic analysis revealed no pathogenic MEFV variant. Colchicine and anakinra 100 mg/day were added to his treatment. He experienced 1-2 abdominal episodes annually between 2014-2019, and APR were normal between attacks. In March 2019, he was admitted to the hospital because of abdominal pain, high APR, and iron deficiency anemia. No gross pathology was observed in endoscopic examination of gastrointestinal tract, but histopathological investigation of the gastric mucosa and terminal ileum showed AA amyloidosis. Multiple aneurysms were detected in renal arteries with angiography. Deep sequencing of the targeted genes revealed homozygous p.Pro251Leu in ADA2 gene and heterozygous p.Thr647Pro in TNFAIP3 gene encoding A20, confirming the molecular diagnosis of DADA2 and HA20. The patient described oral recurrent aphthous ulcers starting from his childhood, but he had no uveitis or genital ulcers. His mother and brother also had recurrent oral aphthous ulcers. Genetic analyses showed heterozygous p.Pro251Leu variant in ADA2 gene in his mother, and heterozygous p.Gln703Lys variant in NLRP3 gene as well as heterozygous p.Thr647Pro TNFAIP3 variant and heterozygous p.Pro251Leu ADA2 in his brother. An improvement in his findings was observed within 2 weeks after switching his anakinra to adalimumab 40 mg every other week. At his last visit in February 2021, the patient had no complaints with normal APR, and urinalysis analysis showed 200 mg/day proteinuria, which was regressed from 3 g/day.ConclusionThis is the first case of AA amyloidosis associated with ADA2 and TNFAIP3 (A20) variants. ADA2 p.Pro251Leu variant has previously been validated as likely pathogenic, and our patient’s clinical findings were mainly compatible with DADA2. On the other hand, TNFAIP3 gene p.Thr647Pro mutation has been reported as variant of unknown significance, but it may have contributed to the DADA2 associated increased risk of amyloidosis. A better response of proteinuria to adalimumab treatment indicates superiority of anti-TNFs in DADA2 patients compared to anti-IL-1 drugs.References[1]Ekinci RMK, Balci S, Bisgin A, et al. Renal amyloidosis in deficiency of adenosine deaminase 2: successful experience with canakinumab. Pediatrics 2018;142.[2]Batu ED, Karadag O, Taskiran EZ, et al. A case series of adenosine deaminase 2-deficient patients emphasizing treatment and genotype-phenotype correlations. The Journal of rheumatology 2015;42:1532-4.Disclosure of InterestsNone declared

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Mortellaro, Alessandra, Matteo Zoccolillo, Cristina Mesa Nuñez, Alessia Brix, Immacolata Brigida, Federica Barzaghi, Serena Scala, et al. "Lentiviral-Mediated Gene Therapy for the Treatment of Adenosine Deaminase 2 Deficiency." Blood 138, Supplement 1 (November 5, 2021): 2937. http://dx.doi.org/10.1182/blood-2021-152127.

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Abstract Adenosine deaminase 2 deficiency (DADA2) is a recently defined inborn error of immunity caused by loss-of-function mutations in the ADA2 gene. Patients suffer from severe manifestations, including early-onset lacunar strokes, intracranial hemorrhages, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic abnormalities. The therapeutic benefit of the current treatments is unsatisfactory. Anti-tumor necrosis factor therapy reduces strokes and systemic inflammation but does not correct cytopenia and bone marrow failure. Allogeneic hematopoietic stem/progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for complications. Therefore, we proposed that autologous HSPC gene therapy may be an alternative curative option for patients who has no compatible donor or cannot receive intense chemotherapy. We performed an in-depth study, using multiparametric flow cytometry, of the bone marrow (BM) cell composition of three adult patients with the hematological phenotype of DADA2. Compared with healthy donors (HDs), patients' BM exhibited a reduced number of mature and immature populations belonging to different hematopoietic lineages. Patients exhibited a substantial reduction in circulating neutrophils and hematopoietic stem cells and progenitor pools in the BM. Severe neutropenia and HSPC defects are direct causes of DADA2. Indeed, ADA2 knock-down in zebrafish - as rodents do not harbor an ADA2 orthologue gene - caused a significant decrease in neutrophil and HSPC numbers, reminiscent of patients' phenotype. Administration of human recombinant ADA2 effectively corrected both neutropenia and defective hematopoiesis in the zebrafish embryo. We used a third-generation LV to restore constitutive ADA2 expression in HSPCs. Transduction of healthy donors' HSPCs allowed efficient delivery of the functional ADA2 enzyme with no toxicity. Supranormal ADA2 expression in healthy donors' and patients' HSPCs was well-tolerated and did not impact HSPC multilineage differentiation potential in vitro and in vivo. We also assessed whether LV-derived ADA2 could correct the hyperinflammatory M1 macrophage phenotype characteristic of DADA2. ADA2 reconstitution in patients' macrophages led to the normalization of IL-6 and TNF release. Similar results were obtained using M1 macrophages differentiated from ADA2-transduced HSPCs. Altogether, our findings indicate that HSPC gene therapy is a promising approach to re-establish stable ADA2 activity and correct the hematological and inflammatory manifestations in patients with DADA2. Disclosures Aiuti: Orchard Therapeutics: Other: PI of clinical trials sponsored by company.

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Le Voyer, Tom, David Boutboul, Albane Ledoux-Pilon, Flore Sicre de Fontbrune, Guilaine Boursier, Sylvain Latour, and Guillaume Le Guenno. "Late-Onset EBV Susceptibility and Refractory Pure Red Cell Aplasia Revealing DADA2." Journal of Clinical Immunology 40, no. 6 (July 8, 2020): 948–53. http://dx.doi.org/10.1007/s10875-020-00812-8.

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Liu, Luyao, Wenjie Wang, Ying Wang, Jia Hou, Wenjing Ying, Xiaoying Hui, Qinhua Zhou, et al. "A Chinese DADA2 patient: report of two novel mutations and successful HSCT." Immunogenetics 71, no. 4 (January 5, 2019): 299–305. http://dx.doi.org/10.1007/s00251-018-01101-w.

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Schnappauf, Oskar, Qing Zhou, Natalia Sampaio Moura, Amanda K. Ombrello, Drew G. Michael, Natalie Deuitch, Karyl Barron, et al. "Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance." Journal of Clinical Immunology 40, no. 6 (July 8, 2020): 917–26. http://dx.doi.org/10.1007/s10875-020-00817-3.

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Khubchandani, Raju, and Ivona Aksentijevich. "Deficiency of Adenosine Deaminase 2 (DADA2) — A New Autoinflammatory Disease with Multisystem Features." Indian Pediatrics 57, no. 11 (August 14, 2020): 1074–75. http://dx.doi.org/10.1007/s13312-020-2041-1.

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Van Der Pol, William J., Ranjit Kumar, Casey D. Morrow, Eugene E. Blanchard, Christopher M. Taylor, David H. Martin, Elliot J. Lefkowitz, and Christina A. Muzny. "In Silico and Experimental Evaluation of Primer Sets for Species-Level Resolution of the Vaginal Microbiota Using 16S Ribosomal RNA Gene Sequencing." Journal of Infectious Diseases 219, no. 2 (August 23, 2018): 305–14. http://dx.doi.org/10.1093/infdis/jiy508.

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V4 sequence reads clustered at 99% identity and assigned to operational taxonomic units using the 99% clustered, extended Greengenes database provided optimal species-level identification of vaginal bacteria. This method provided results similar to those obtained with DADA2 and/or using the SILVA database.

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Guelman, Sebastián, Tamaki Suganuma, Laurence Florens, Selene K. Swanson, Cheri L. Kiesecker, Thomas Kusch, Scott Anderson, et al. "Host Cell Factor and an Uncharacterized SANT Domain Protein Are Stable Components of ATAC, a Novel dAda2A/dGcn5-Containing Histone Acetyltransferase Complex in Drosophila." Molecular and Cellular Biology 26, no. 3 (February 1, 2006): 871–82. http://dx.doi.org/10.1128/mcb.26.3.871-882.2006.

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ABSTRACT Gcn5 is a conserved histone acetyltransferase (HAT) found in a number of multisubunit complexes from Saccharomyces cerevisiae, mammals, and flies. We previously identified Drosophila melanogaster homologues of the yeast proteins Ada2, Ada3, Spt3, and Tra1 and showed that they associate with dGcn5 to form at least two distinct HAT complexes. There are two different Ada2 homologues in Drosophila named dAda2A and dAda2B. dAda2B functions within the Drosophila version of the SAGA complex (dSAGA). To gain insight into dAda2A function, we sought to identify novel components of the complex containing this protein, ATAC (Ada two A containing) complex. Affinity purification and mass spectrometry revealed that, in addition to dAda3 and dGcn5, host cell factor (dHCF) and a novel SANT domain protein, named Atac1 (ATAC component 1), copurify with this complex. Coimmunoprecipitation experiments confirmed that these proteins associate with dGcn5 and dAda2A, but not with dSAGA-specific components such as dAda2B and dSpt3. Biochemical fractionation revealed that ATAC has an apparent molecular mass of 700 kDa and contains dAda2A, dGcn5, dAda3, dHCF, and Atac1 as stable subunits. Thus, ATAC represents a novel histone acetyltransferase complex that is distinct from previously purified Gcn5/Pcaf-containing complexes from yeast and mammalian cells.

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Lee, Pui Y., Erinn S. Kellner, Yuelong Huang, Elissa Furutani, Zhengping Huang, Wayne Bainter, Mohammed F. Alosaimi, et al. "Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)." Journal of Allergy and Clinical Immunology 145, no. 6 (June 2020): 1664–72. http://dx.doi.org/10.1016/j.jaci.2019.12.908.

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Meyts, Isabelle, and Ivona Aksentijevich. "Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment." Journal of Clinical Immunology 38, no. 5 (June 27, 2018): 569–78. http://dx.doi.org/10.1007/s10875-018-0525-8.

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Sasa, Ghadir S., M. Tarek Elghetany, Katie Bergstrom, Sarah Nicholas, Ryan Himes, Robert A. Krance, Michael Hershfield, Joris van Montfrans, and Alison Bertuch. "Adenosine Deaminase 2 Deficiency As a Cause of Pure Red Cell Aplasia Mimicking Diamond Blackfan Anemia." Blood 126, no. 23 (December 3, 2015): 3615. http://dx.doi.org/10.1182/blood.v126.23.3615.3615.

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Abstract Diamond Blackfan anemia (DBA) is an inherited pure red cell aplasia. Most cases present in the first year of life with elevation in erythrocyte adenosine deaminase (eADA) and frequently with increased mean corpuscular volume (MCV) and hemoglobin F (hgb F). Approximately 70 percent of cases are due to a mutation in one of several ribosomal protein (RP) genes or in GATA1, whereas the remaining cases are genetically uncharacterized. Here we report a child born with severe anemia and diagnosed with DBA at 2 months of age. His bone marrow was normocellular with a paucity of erythroid progenitors and scattered lymphocytes. An eADA level was not obtained prior to the first red cell transfusion. He was red cell transfusion dependent and his anemia did not respond to a steroid trial. His 4 year old sister, who had normal hemoglobin, MCV, hgb F, and eADA measurements, served as his HLA identical donor for hematopoietic stem cell transplantation (HSCT). HSCT resulted in 100% donor chimerism, but red cell engraftment was not achieved. He subsequently underwent a mismatched unrelated HSCT with trilineage engraftment. Ten years later, at the age of 14 years, the sister presented with profound hypoproductive normocytic anemia. The bone marrow showed absence of erythroid precursors and presence of lymphoid aggregates. Findings of immunodeficiency included numerous cutaneous warts, recurrent aphthous ulcers, Epstein Barr virus (EBV) reactivation, low IgM, and low numbers and percentages of CD19+ and CD3-56+16+ lymphocytes. The anemia and reticulocytopenia persisted despite resolution of EBV reactivation. Upon her presentation, levels of iron, ferritin, transferrin saturation, and liver transaminases were elevated. A liver biopsy obtained after transfusion of a total of 60 ml/kg packed red blood cells demonstrated 4.8 mg Fe/g dry liver weight with stage 2 portal fibrosis. Targeted DNA sequencing studies performed on the affected sister were negative for single nucleotide variants in any of 12 RP genes previously implicated in DBA and a genome wide chromosome microarray was normal. Whole exome analysis of her and her parents demonstrated that she carried compound heterozygous variants in CECR1 (cat eye syndrome chromosome region, candidate 1). The variant p.R169Q had been previously reported as pathogenic, while the p.G358R variant was of uncertain significance. These variants are present at frequencies of 4.9X10-4 and 2.6X10-5 in the Exome Aggregation Consortium database, respectively. Analysis of buccal swab DNA of the proband showed the same biallelic variants. An unaffected 16-year-old sibling had a normal genotype. CECR1 encodes adenosine deaminase 2 (ADA2) and ADA2 levels in the plasma of the affected sister were markedly low, consistent with a deficiency state. CECR1 is highly expressed in cells of myeloid origin and ADA2 is a secreted protein implicated in macrophage differentiation and proliferation. Deficiency of ADA2 (DADA2) results in aberrant monocyte differentiation favoring M1 over M2 macrophages, thereby resulting in a proinflammatory state. Recent descriptions of patients with DADA2 due to CECR1 mutations reported a spectrum of phenotypes including intermittent fevers, lacunar stroke in childhood, livedoid rash, polyarteritis nodosa, and immunodeficiency with B lymphopenia and low IgM levels. Our cases are similar to the report of one of two brothers, homozygous for CECR1 p.R169Q, described by van Montfrans, et al,. (NEJM, 2014). The eldest was given a diagnosis of atypical DBA (refractory pure red cell aplasia) in infancy and underwent a HSCT from his asymptomatic, HLA identical brother. This HSCT resulted in non-engraftment, necessitating a subsequent unrelated donor HSCT. The younger sibling donor later developed hepatosplenomegaly, profound lymphopenia, and evidence of an inflammatory state. Together, these three cases support pure red cell aplasia as a presentation of DADA2 and that this may be confused with DBA, particularly when manifest in infancy. We propose DADA2 should be considered in patients with genetically uncharacterized DBA. Differentiating features to suggest DADA2 may include normal eADA, MCV, and hgb F levels and findings of associated immunodeficiency. Additionally, the macrophage activation due to DADA2 may have played a role in the iron overload observed in our second patient prior to any red cell transfusion. Disclosures No relevant conflicts of interest to declare.

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Nearing, Jacob T., Gavin M. Douglas, André M. Comeau, and Morgan G. I. Langille. "Denoising the Denoisers: an independent evaluation of microbiome sequence error-correction approaches." PeerJ 6 (August 8, 2018): e5364. http://dx.doi.org/10.7717/peerj.5364.

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High-depth sequencing of universal marker genes such as the 16S rRNA gene is a common strategy to profile microbial communities. Traditionally, sequence reads are clustered into operational taxonomic units (OTUs) at a defined identity threshold to avoid sequencing errors generating spurious taxonomic units. However, there have been numerous bioinformatic packages recently released that attempt to correct sequencing errors to determine real biological sequences at single nucleotide resolution by generating amplicon sequence variants (ASVs). As more researchers begin to use high resolution ASVs, there is a need for an in-depth and unbiased comparison of these novel “denoising” pipelines. In this study, we conduct a thorough comparison of three of the most widely-used denoising packages (DADA2, UNOISE3, and Deblur) as well as an open-reference 97% OTU clustering pipeline on mock, soil, and host-associated communities. We found from the mock community analyses that although they produced similar microbial compositions based on relative abundance, the approaches identified vastly different numbers of ASVs that significantly impact alpha diversity metrics. Our analysis on real datasets using recommended settings for each denoising pipeline also showed that the three packages were consistent in their per-sample compositions, resulting in only minor differences based on weighted UniFrac and Bray–Curtis dissimilarity. DADA2 tended to find more ASVs than the other two denoising pipelines when analyzing both the real soil data and two other host-associated datasets, suggesting that it could be better at finding rare organisms, but at the expense of possible false positives. The open-reference OTU clustering approach identified considerably more OTUs in comparison to the number of ASVs from the denoising pipelines in all datasets tested. The three denoising approaches were significantly different in their run times, with UNOISE3 running greater than 1,200 and 15 times faster than DADA2 and Deblur, respectively. Our findings indicate that, although all pipelines result in similar general community structure, the number of ASVs/OTUs and resulting alpha-diversity metrics varies considerably and should be considered when attempting to identify rare organisms from possible background noise.

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Maramattom, BobyVarkey, Ashin Varghese, and Joe Thomas. "‘More than just skin in the game’. DADA2 autoinflammatory syndrome and stroke in the young." Annals of Indian Academy of Neurology 24, no. 3 (2021): 410. http://dx.doi.org/10.4103/aian.aian_716_20.

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Kumar, V., D. Thakker, P. Gupta, and S. Nair. "POSB418 Management of Patients with Deficiency of Adenosine Deaminase 2 (DADA2): A Systematic Literature Review." Value in Health 25, no. 1 (January 2022): S262. http://dx.doi.org/10.1016/j.jval.2021.11.1281.

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Xu, Jiahui, Jianlin Han, Hua Su, Changyu Zhu, Zijing Quan, Lei Wu, and Zhenzhen Yi. "Diversity Patterns of Protists Are Highly Affected by Methods Disentangling Biological Variants: A Case Study in Oligotrich (s.l.) Ciliates." Microorganisms 10, no. 5 (April 27, 2022): 913. http://dx.doi.org/10.3390/microorganisms10050913.

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Protists are a dominant group in marine microplankton communities and play important roles in energy flux and nutrient cycling in marine ecosystems. Environmental sequences produced by high-throughput sequencing (HTS) methods are increasingly used for inferring the diversity and distribution patterns of protists. However, studies testing whether methods disentangling biological variants affect the diversity and distribution patterns of protists using field samples are insufficient. Oligotrich (s.l.) ciliates are one group of the abundant and dominant planktonic protists in coastal waters and open oceans. Using oligotrich (s.l.) ciliates in field samples as an example, the present study indicates that DADA2 performs better than SWARM, UNOISE, UPARSE, and UCLUST for inferring diversity patterns of oligotrich (s.l.) ciliates in the Pearl River Estuary and surrounding regions. UPARSE and UNOISE might underestimate species richness. SWARM might not be suitable for the resolution of alpha diversity owing to its rigorous clustering and sensitivity to sequence variations. UCLUST with 99% clustering threshold overestimates species richness, and the beta diversity pattern inferred by DADA2 is more reasonable than that of the other methods. Additionally, salinity is shown to be one of the key factors responsible for variations in the community distribution of ciliates, but infrequent marine–freshwater transitions occurred during evolutionary terms of this group.

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Albalawi, Reem, Ehab Hanafy, Haifa Alnafea, Mohammed Altowijiry, Shaima Riyad, Fadwa Abufara, and Naif Albolowi. "Novel Adenosine Deaminase 2 (ADA2) Mutations Associated With Hematological Manifestations." Journal of Investigative Medicine High Impact Case Reports 9 (January 2021): 232470962110567. http://dx.doi.org/10.1177/23247096211056770.

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Recent progress in laboratory techniques, particularly, identification of novel disease-causing genes, has led to the detection of different gene mutations that might be implicated in the pathogenesis of different hematological disorders like pure red cell aplasia (PRCA) and neutropenia. An autoinflammatory disorder known as deficiency of adenosine deaminase 2 (DADA2) has been recently noticed to present with variable hematologic abnormalities. We report 2 patients who presented with hematologic abnormalities in which 2 ADA2 gene mutations were detected. The first case is a 5-year-old girl who presented with severe PRCA and autoimmune hemolytic anemia without any other manifestation of DADA2 that resulted from a novel CECR1 c.714_738dup, p. (Ala247Glnfs*16) homozygous variant. The second case is a 10-year-old boy, known to have Hodgkin lymphoma and was under follow-up for 6 years; he presented with persistent neutropenia and was discovered to be homozygous for ADA2 c.1447_1451del, p. (Ser483Profs*5). In conclusion, we report two different novels ADA2 variants in two children; the first presented with PRCA and the second presented with persistent neutropenia. This report aims to raise the concerns regarding the use of genetic testing in different hematologic diseases with indefinite etiology, as it will lead to the best therapeutic strategies without the need for unnecessary interventions.

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Harbuzov, Zoya, Valeria Farberova, Moshe Tom, Alberto Pallavicini, David Stanković, Tamar Lotan, and Hadas Lubinevsky. "Amplicon sequence variant-based meiofaunal community composition revealed by DADA2 tool is compatible with species composition." Marine Genomics 65 (October 2022): 100980. http://dx.doi.org/10.1016/j.margen.2022.100980.

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Thi Nhung, Doan, and Bui Van Ngoc. "Bioinformatic approaches for analysis of coral-associated bacteria using R programming language." Vietnam Journal of Biotechnology 18, no. 4 (May 24, 2021): 733–43. http://dx.doi.org/10.15625/1811-4989/18/4/15320.

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Recent advances in metagenomics and bioinformatics allow the robust analysis of the composition and abundance of microbial communities, functional genes, and their metabolic pathways. So far, there has been a variety of computational/statistical tools or software for analyzing microbiome, the common problems that occurred in its implementation are, however, the lack of synchronization and compatibility of output/input data formats between such software. To overcome these challenges, in this study context, we aim to apply the DADA2 pipeline (written in R programming language) instead of using a set of different bioinformatics tools to create our own workflow for microbial community analysis in a continuous and synchronous manner. For the first effort, we tried to investigate the composition and abundance of coral-associated bacteria using their 16S rRNA gene amplicon sequences. The workflow or framework includes the following steps: data processing, sequence clustering, taxonomic assignment, and data visualization. Moreover, we also like to catch readers’ attention to the information about bacterial communities living in the ocean as most marine microorganisms are unculturable, especially residing in coral reefs, namely, bacteria are associated with the coral Acropora tenuis in this case. The outcomes obtained in this study suggest that the DADA2 pipeline written in R programming language is one of the potential bioinformatics approaches in the context of microbiome analysis other than using various software. Besides, our modifications for the workflow execution help researchers to illustrate metagenomic data more easily and systematically, elucidate the composition, abundance, diversity, and relationship between microorganism communities as well as to develop other bioinformatic tools more effectively.

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Caorsi, Roberta, Federica Penco, Alice Grossi, Antonella Insalaco, Alessia Omenetti, Maria Alessio, Giovanni Conti, et al. "ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study." Annals of the Rheumatic Diseases 76, no. 10 (May 18, 2017): 1648–56. http://dx.doi.org/10.1136/annrheumdis-2016-210802.

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Journal articles on the topic 'Dada2'

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