title: Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.
abstract: Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations inPIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657XPIK3R1mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus,PIK3R1C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.
authors.affiliation: 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.
authors.forename: Isabel
authors.initials: I
authors.lastname: Huang-Doran
authors.affiliation: 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.
authors.forename: Patsy
authors.initials: P
authors.lastname: Tomlinson
authors.affiliation: Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.affiliation: 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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gast
authors.affiliation: Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Sleigh
authors.affiliation: Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Bottomley
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Harris
authors.affiliation: Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Allan
authors.initials: A
authors.lastname: Daly
authors.affiliation: 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.
authors.forename: Nuno
authors.initials: N
authors.lastname: Rocha
authors.affiliation: Inositide Laboratory, Babraham Institute, Cambridge, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Rudge
authors.affiliation: Inositide Laboratory, Babraham Institute, Cambridge, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clark
authors.affiliation: 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.
authors.forename: Albert
authors.initials: A
authors.lastname: Kwok
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.|Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.affiliation: Department of Clinical Genetics, Glan Clwyd Hospital, Rhyl, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: McCann
authors.affiliation: Department of Pediatrics, Children's Hospital, Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Müksch
authors.affiliation: Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dattani
authors.affiliation: Pediatric Endocrine Unit, S.Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Zucchini
authors.affiliation: Inositide Laboratory, Babraham Institute, Cambridge, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Wakelam
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors.forename: Lazaros C
authors.initials: LC
authors.lastname: Foukas
authors.affiliation: 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.
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
authors.affiliation: Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Rinki
authors.initials: R
authors.lastname: Murphy
authors.affiliation: 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.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: 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.|Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: 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.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes; D000293:Adolescent; D000818:Animals; D002648:Child; D058543:Class Ia Phosphatidylinositol 3-Kinase; D050171:Dyslipidemias; D005234:Fatty Liver; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010766:Phosphorylation
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; C588001:PIK3R1 protein, human