Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant
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Abstract
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.
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PIK3R1 mutations produce different phenotypes depending on the variant and domain of the protein affected.
“One striking example is PIK3R1, which encodes a regulatory subunit of phosphoinositide 3-kinase (PI3K), a crucial player in signalling from many types of hormone receptor: early nonsense PIK3R1 mutations produce immunodeficiency and enhance insulin sensitivity, while nonsense mutations late in the gene cause severe insulin resistance and developmental defects. Furthermore, missense mutations pro”
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Massively parallel functional genomic assays in endocrinology: from promise to delivery
Xu, J., Aslanzadeh, V., Kudla, G., & Semple, R. K. (2026) · Journal of Molecular Endocrinology · doi:10.1530/jme-25-0134
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- Authors
- Tomlinson, P. R., Knox, R. G., Perisic, O., Su, H., Brierley, G. V., Williams, R. L., & Semple, R. K.
- Affiliations
- University of Cambridge (GB)
- MRC Laboratory of Molecular Biology
- National Institutes of Health (US)
- Royal Veterinary College (GB)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Semple, Robert K
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2025-01-21
- Volume
- 13
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC10705566
- OpenAlex
- W4388299572
- Cited by
- 2
- References
- 1
- Citations by year
- 2026: 1 · 2025: 1
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, public-domain)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (10.35802/210752, 10.35802/102356)
- Medical Research Council (MC_UU_12012/5, MC_U105184308)
- National Institute of Allergy and Infectious Diseases (Intramural)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- PIK3R1, phosphatidylinositol 3-kinase, p110δ, p110α, dominant negative effect, immunodeficiency, SHORT syndrome, genotype-phenotype correlation, insulin resistance, IRS-1, insulin receptor substrate 2, heterodimerization, dermal fibroblasts, preadipocytes, gain-of-function mutations
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