Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2

Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2 Publisher Pubmed

Nguyen T^{1, 2} ; Lau A^{1, 2} ; Bier J^{1, 2} ; Cooke KC³ ; Lenthall H¹ ; Ruizdiaz S¹ ; Avery DT¹ ; Brigden H¹ ; Zahra D¹ ; Sewell WA^{1, 2} ; Droney L⁴ ; Okada S⁵ ; Asano T⁵ ; Abolhassani H^{6, 7} Show All Authors

Nguyen T^{1, 2}
Lau A^{1, 2}
Bier J^{1, 2}
Cooke KC³
Lenthall H¹
Ruizdiaz S¹
Avery DT¹
Brigden H¹
Zahra D¹
Sewell WA^{1, 2}
Droney L⁴
Okada S⁵
Asano T⁵
Abolhassani H^{6, 7}
Chavoshzadeh Z⁸
Abraham RS⁹
Rajapakse N¹⁰
Klee EW¹¹
Church JA^{12, 13}
Williams A^{14, 15, 20}
Wong M^{14, 15, 16}
Burkhart C¹⁷
Uzel G¹⁸
Croucher DR^{1, 2}
James DE^{3, 19}
Ma CS^{1, 2, 14}
Brink R^{1, 2}
Tangye SG^{1, 2, 14}
Deenick EK^{1, 2, 14}

Show Affiliations

1. Garvan Institute of Medical Research, Darlinghurst, Australia
2. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Kensington, Australia
3. Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
4. Department of Clinical Immunology, Royal Brisbane and Womenâ€™s Hospital, Brisbane, Australia
5. Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
6. Department of Biosciences and Nutrition, Division of Clinical Immunology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
7. Research Center for Immunodeficiencies, Childrenâ€™s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
8. Pediatric Infections Research Center, Mofid Childrenâ€™s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
9. Department of Pathology and Laboratory Medicine, Nationwide Childrenâ€™s Hospital, Columbus, OH, United States
10. Department of Pediatric and Adolescent Medicine, Division of Pediatric Infectious Diseases, Mayo Clinic, Rochester, MN, United States
11. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
12. Division of Clinical Immunology and Allergy, Childrenâ€™s Hospital of Los Angeles, Los Angeles, CA, United States
13. Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
14. Clinical Immunogenomics Research Consortium Australasia, Sydney, Australia
15. Childrenâ€™s Hospital at Westmead, Westmead, Australia
16. Faculty of Medicine, University of Sydney, Sydney, Australia
17. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland
18. Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
19. School of Medical Sciences, University of Sydney, Sydney, Australia
20. Central Clinical School, University of Sydney, Sydney, Australia

Source: Journal of Experimental Medicine Published:2023

Abstract

Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-offunction (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients’ immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies. © 2023 Nguyen et al.

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Style	Citing Format
MLA	Nguyen T, et al.. "Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2." Journal of Experimental Medicine, vol. 220, no. 6, 2023, pp. -.
APA	Nguyen T, Lau A, Bier J, Cooke KC, Lenthall H, Ruizdiaz S, Avery DT, Brigden H, Zahra D, Sewell WA, Droney L, Okada S, Asano T, Abolhassani H, Chavoshzadeh Z, Abraham RS, Rajapakse N, Klee EW, Church JA, ... Deenick EK (2023). Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2. Journal of Experimental Medicine, 220(6), -.
Chicago	Nguyen T, Lau A, Bier J, Cooke KC, Lenthall H, Ruizdiaz S, Avery DT, et al.. "Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2." Journal of Experimental Medicine 220, no. 6 (2023): -.
Harvard	Nguyen T et al. (2023) 'Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2', Journal of Experimental Medicine, 220(6), pp. -.
Vancouver	Nguyen T, Lau A, Bier J, Cooke KC, Lenthall H, Ruizdiaz S, et al.. Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2. Journal of Experimental Medicine. 2023;220(6):-.
BibTex	@article{ author = {Nguyen T and Lau A and Bier J and Cooke KC and Lenthall H and Ruizdiaz S and Avery DT and Brigden H and Zahra D and Sewell WA and Droney L and Okada S and Asano T and Abolhassani H and Chavoshzadeh Z and Abraham RS and Rajapakse N and Klee EW and Church JA and Williams A and Wong M and Burkhart C and Uzel G and Croucher DR and James DE and Ma CS and Brink R and Tangye SG and Deenick EK}, title = {Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2}, journal = {Journal of Experimental Medicine}, volume = {220}, number = {6}, pages = {-}, year = {2023} }
RIS	TY - JOUR AU - Nguyen T AU - Lau A AU - Bier J AU - Cooke KC AU - Lenthall H AU - Ruizdiaz S AU - Avery DT AU - Brigden H AU - Zahra D AU - Sewell WA AU - Droney L AU - Okada S AU - Asano T AU - Abolhassani H AU - Chavoshzadeh Z AU - Abraham RS AU - Rajapakse N AU - Klee EW AU - Church JA AU - Williams A AU - Wong M AU - Burkhart C AU - Uzel G AU - Croucher DR AU - James DE AU - Ma CS AU - Brink R AU - Tangye SG AU - Deenick EK TI - Human Pik3r1 Mutations Disrupt Lymphocyte Differentiation to Cause Activated Pi3kδ Syndrome 2 JO - Journal of Experimental Medicine VL - 220 IS - 6 SP - EP - PY - 2023 ER -

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