Diagnostic implications and correlates of plasma ADA2 activity and ADA2 variants

Jian Yue^#^{1

2}, Courtney E LeSon^#¹, Casey A Rimland^#^{1

3}, Kailey Brodeur^{1

4}, Rachel Weng¹, Evan E Hsu¹, Michael T Lam¹, Manpreet Meyer¹, Seigo Okada^{1

5}, Andrew L D Hsu¹, Musaab A Alhezam¹, Megan M Perron¹, Olha Halyabar¹, Fatma Dedeoglu¹, Peter A Nigrovic^{1

3}, Akiko Shimamura⁶, R Grant Rowe⁶, Megan A Cooper⁷, Tiphanie P Vogel⁸, Miriah Gillispie-Taylor⁹, Rosemary Peterson¹⁰, Clara Lin¹¹, Katherine D Nowicki¹¹, Kaylee Dollerschell¹², Taizo A Nakano¹³, Roxane Labrosse¹⁴, Alexis-Virgil Cochino^{15

16}, Andreea Ioan^{15

16}, Leonardo Oliveira Mendonca^{17

18}, Samar Freschi Barros^{17

18}, Jorge Kalil^{17

18}, Javier Perez Rojas¹⁹, Alicia Diaz Kuan²⁰, Eric S Sobel²¹, Taha Moussa²², Samuel Shang Ming Lee²³, Li Wearn Koh²³, Archana Khan²⁴, Sodality Sutnga²⁴, Raju Khubchandani²⁴, Walaa Shoman²⁵, Yasmine El Chazli²⁶, Benzeeta Pinto²⁷, Chengappa Kavadichanda²⁸, Roshini S Abraham²⁹, Xiangwei Sun³⁰, Qing Zhou³⁰, Gsrsnk Naidu³¹, Aman Sharma³¹, Carl Esperanzate³², Daniel L Kastner³², Ivona Aksentijevich³², Susan J Kelly³³, Michael Hershfield³⁴, Teresa K Tarrant^{35

36}, Pui Y Lee¹

Affiliations

¹ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Guangzhou, China.
³ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Medical Scientist Training Program, UMass Chan Medical School, Worcester, MA, USA.
⁵ Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
⁶ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
⁷ Division of Rheumatology & Immunology, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.
⁸ Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, USA.
⁹ Division of Rheumatology, Department of Pediatrics, Huffington Department of Education, Innovation, and Technology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
¹⁰ Pediatric Rheumatology, Dell Childrens Medical Group, University of Texas at Austin Dell Medical School, Austin, TX, USA.
¹¹ Department of Pediatrics, Section of Pediatric Rheumatology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹² Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹³ Center for Cancer and Blood Disorders, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁴ Department of Pediatrics, Section of Allergy and Clinical Immunology, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada.
¹⁵ UMF Carol Davila, Bucharest, Romania.
¹⁶ INSMC Alessandrescu Rusescu, Bucharest, Romania.
¹⁷ Discipline of clinical immunology and allergy, faculdade de medicina da universidade de São Paulo, São Paulo, Brazil.
¹⁸ Laboratory for Medical Investigation (LIM-19), instituto do coração da faculdade de medicina da universidade de São Paulo, São Paulo, Brazil.
¹⁹ Division of Clinical Immunology and Allergy, Department of Internal Medicine, Guillermo Almenara Irigoyen National Hospital - EsSalud, Lima, Peru.
²⁰ Genetica Molecular, Universidad Peruana Cayetano Heredia, Peru.
²¹ Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
²² Section of Pediatric Rheumatology, University of Florida College of Medicine - Jacksonville, Jacksonville, FL, USA.
²³ Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore.
²⁴ Pediatric Rheumatology, SRCC Children's Hospital, Mumbai, India.
²⁵ Pediatric Immunology and Rheumatology Unit, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
²⁶ Pediatric Hematology Unit, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
²⁷ Department of Clinical Immunology and Rheumatology, St John's Medical College Bengaluru, India.
²⁸ Clinical Immunology and Rheumatology, RheumaCARE, Mysuru, India.
²⁹ Diagnostic Immunology Laboratory, Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
³⁰ Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
³¹ Clinical Immunology and Rheumatology Division, Department of Internal Medicine, PGIMER, Chandigarh, India.
³² Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
³³ Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
³⁴ Department of Medicine and Biochemistry, Duke University School of Medicine, Durham, NC, USA.
³⁵ Departments of Medicine and Pathology, Duke University School of Medicine, Durham, NC, USA.
³⁶ Durham Veteran's Health Administration Health Care System, Durham, NC, USA.

^# Contributed equally.

PMID: 41147740
DOI: 10.1002/art.43412

Diagnostic implications and correlates of plasma ADA2 activity and ADA2 variants

Jian Yue et al. Arthritis Rheumatol. 2025.

. 2025 Oct 28.

doi: 10.1002/art.43412. Online ahead of print.

Authors

Affiliations

¹ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Guangzhou, China.
³ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Medical Scientist Training Program, UMass Chan Medical School, Worcester, MA, USA.
⁵ Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
⁶ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
⁷ Division of Rheumatology & Immunology, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA.
⁸ Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, USA.
⁹ Division of Rheumatology, Department of Pediatrics, Huffington Department of Education, Innovation, and Technology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
¹⁰ Pediatric Rheumatology, Dell Childrens Medical Group, University of Texas at Austin Dell Medical School, Austin, TX, USA.
¹¹ Department of Pediatrics, Section of Pediatric Rheumatology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹² Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹³ Center for Cancer and Blood Disorders, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁴ Department of Pediatrics, Section of Allergy and Clinical Immunology, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada.
¹⁵ UMF Carol Davila, Bucharest, Romania.
¹⁶ INSMC Alessandrescu Rusescu, Bucharest, Romania.
¹⁷ Discipline of clinical immunology and allergy, faculdade de medicina da universidade de São Paulo, São Paulo, Brazil.
¹⁸ Laboratory for Medical Investigation (LIM-19), instituto do coração da faculdade de medicina da universidade de São Paulo, São Paulo, Brazil.
¹⁹ Division of Clinical Immunology and Allergy, Department of Internal Medicine, Guillermo Almenara Irigoyen National Hospital - EsSalud, Lima, Peru.
²⁰ Genetica Molecular, Universidad Peruana Cayetano Heredia, Peru.
²¹ Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
²² Section of Pediatric Rheumatology, University of Florida College of Medicine - Jacksonville, Jacksonville, FL, USA.
²³ Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore.
²⁴ Pediatric Rheumatology, SRCC Children's Hospital, Mumbai, India.
²⁵ Pediatric Immunology and Rheumatology Unit, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
²⁶ Pediatric Hematology Unit, Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
²⁷ Department of Clinical Immunology and Rheumatology, St John's Medical College Bengaluru, India.
²⁸ Clinical Immunology and Rheumatology, RheumaCARE, Mysuru, India.
²⁹ Diagnostic Immunology Laboratory, Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
³⁰ Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
³¹ Clinical Immunology and Rheumatology Division, Department of Internal Medicine, PGIMER, Chandigarh, India.
³² Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
³³ Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
³⁴ Department of Medicine and Biochemistry, Duke University School of Medicine, Durham, NC, USA.
³⁵ Departments of Medicine and Pathology, Duke University School of Medicine, Durham, NC, USA.
³⁶ Durham Veteran's Health Administration Health Care System, Durham, NC, USA.

^# Contributed equally.

PMID: 41147740
DOI: 10.1002/art.43412

Abstract

Objectives: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease manifested as polyarteritis nodosa, stroke, and bone marrow failure. Leveraging an international cohort of 200 DADA2 cases, we aimed to characterize the diagnostic utility of a plasma ADA2 enzyme activity assay and understand the implications of residual ADA2 activity.

Methods: Data were collected from individuals who underwent ADA2 testing from 2018 to 2025. Plasma ADA2 activity was determined using an established spectrophotometric assay. ADA2 variants were analyzed in transfected cells by enzyme assay and western blotting.

Results: We determined that plasma ADA2 activity is 99.0%/96.0% sensitive, and 99.7%/98.8% specific in distinguishing genetically confirmed DADA2 cases from controls and carriers, respectively. Eighteen individuals with DADA2 (9%) possessed detectable ADA2 activity, including several cases with levels seen in carriers. Residual ADA2 activity was associated with the vasculitis / inflammatory phenotype but not with disease severity. Genotype analysis revealed that 14/18 cases with residual plasma activity possessed at least one hypomorphic missense variant with >20% residual ADA2 function when overexpressed in 293T cells, often occurring in trans with a more deleterious variant. In vitro analysis revealed that missense ADA2 variants exert variable dominant-negative effects by forming large intracellular protein aggregates via disulfide bond formation at a cysteine residue (Cys408).

Conclusion: We confirmed the utility of plasma ADA2 activity as a diagnostic assay and showed that the inflammatory phenotype of DADA2 occurred in cases with residual activity. In vitro findings illustrate potential interactions of ADA2 variants to synergistically disrupt protein function.

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Diagnostic implications and correlates of plasma ADA2 activity and ADA2 variants

Affiliations

Diagnostic implications and correlates of plasma ADA2 activity and ADA2 variants

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources

Research Materials