Search: id:"swepub:oai:prod.swepub.kib.ki.se:152588237" >
Human PIK3R1 mutati...
Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2
- Article/chapterEnglish2023
Publisher, publication year, extent ...
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2023-03-21
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Rockefeller University Press,2023
Numbers
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LIBRIS-ID:oai:prod.swepub.kib.ki.se:152588237
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http://kipublications.ki.se/Default.aspx?queryparsed=id:152588237URI
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https://doi.org/10.1084/jem.20221020DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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-of-function (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.
Added entries (persons, corporate bodies, meetings, titles ...)
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Lau, A
(author)
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Bier, J
(author)
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Cooke, KC
(author)
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Lenthall, H
(author)
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Ruiz-Diaz, S
(author)
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Avery, DT
(author)
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Brigden, H
(author)
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Zahra, D
(author)
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Sewell, WA
(author)
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Droney, L
(author)
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Okada, S
(author)
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Asano, T
(author)
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Abolhassani, HKarolinska Institutet
(author)
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Chavoshzadeh, Z
(author)
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Abraham, RS
(author)
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Rajapakse, N
(author)
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Klee, EW
(author)
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Church, JA
(author)
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Williams, A
(author)
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Wong, M
(author)
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Burkhart, C
(author)
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Uzel, G
(author)
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Croucher, DR
(author)
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James, DE
(author)
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Ma, CS
(author)
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Brink, R
(author)
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Tangye, SG
(author)
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Deenick, EK
(author)
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Karolinska Institutet
(creator_code:org_t)
Related titles
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In:The Journal of experimental medicine: Rockefeller University Press220:61540-95380022-1007
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- By the author/editor
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Nguyen, T
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Lau, A
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Bier, J
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Cooke, KC
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Lenthall, H
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Ruiz-Diaz, S
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show more...
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Avery, DT
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Brigden, H
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Zahra, D
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Sewell, WA
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Droney, L
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Okada, S
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Asano, T
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Abolhassani, H
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Chavoshzadeh, Z
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Abraham, RS
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Rajapakse, N
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Klee, EW
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Church, JA
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Williams, A
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Wong, M
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Burkhart, C
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Uzel, G
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Croucher, DR
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James, DE
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Ma, CS
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Brink, R
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Tangye, SG
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Deenick, EK
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The Journal of e ...
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Karolinska Institutet