Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant
Patsy R Tomlinson,
Rachel G Knox,
Olga Perisic,
Helen Su,
Gemma V Brierley,
Roger L Williams,
Robert K Semple
Affiliations
Patsy R Tomlinson
The 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
Rachel G Knox
The 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 Kingdom
Olga Perisic
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
Helen Su
Laboratory of Clinical Immunology & Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, United States
Gemma V Brierley
The 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 Kingdom
The 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 Kingdom
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.
