Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant
PIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous los...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/94420 |
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| author | Patsy R Tomlinson Rachel G Knox Olga Perisic Helen Su Gemma V Brierley Roger L Williams Robert K Semple |
| author_facet | Patsy R Tomlinson Rachel G Knox Olga Perisic Helen Su Gemma V Brierley Roger L Williams Robert K Semple |
| author_sort | Patsy R Tomlinson |
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| description | PIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes. |
| format | Article |
| id | doaj-art-6ef8193e2aa54dc7b4bb81d70c0a0e57 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-6ef8193e2aa54dc7b4bb81d70c0a0e572025-01-21T12:48:58ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.94420Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variantPatsy R Tomlinson0Rachel G Knox1Olga Perisic2Helen Su3Gemma V Brierley4Roger L Williams5https://orcid.org/0000-0001-7754-4207Robert K Semple6https://orcid.org/0000-0001-6539-3069The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United KingdomThe University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomLaboratory of Clinical Immunology & Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, United StatesThe University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; Department of Comparative Biomedical Science, The Royal Veterinary College, London, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomThe University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom; The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United KingdomPIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes.https://elifesciences.org/articles/94420PIK3R1immunodeficiencyAPDS2SHORT syndromeinsulin resistancephosphoinositide 3-kinase |
| spellingShingle | Patsy R Tomlinson Rachel G Knox Olga Perisic Helen Su Gemma V Brierley Roger L Williams Robert K Semple Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant eLife PIK3R1 immunodeficiency APDS2 SHORT syndrome insulin resistance phosphoinositide 3-kinase |
| title | Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant |
| title_full | Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant |
| title_fullStr | Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant |
| title_full_unstemmed | Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant |
| title_short | Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant |
| title_sort | paradoxical dominant negative activity of an immunodeficiency associated activating pik3r1 variant |
| topic | PIK3R1 immunodeficiency APDS2 SHORT syndrome insulin resistance phosphoinositide 3-kinase |
| url | https://elifesciences.org/articles/94420 |
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