title: KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.
abstract: Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Pearce
authors.forename: Neli
authors.initials: N
authors.lastname: Atanassova
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Banton
authors.forename: Bill
authors.initials: B
authors.lastname: Bottomley
authors.forename: Agatha A
authors.initials: AA
authors.lastname: van der Klaauw
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Revelli
authors.forename: Audrey
authors.initials: A
authors.lastname: Hendricks
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Elana
authors.initials: E
authors.lastname: Henning
authors.forename: Deon
authors.initials: D
authors.lastname: Doree
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jeter-Jones
authors.forename: Sumedha
authors.initials: S
authors.lastname: Garg
authors.forename: Elena G
authors.initials: EG
authors.lastname: Bochukova
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bounds
authors.forename: Sofie
authors.initials: S
authors.lastname: Ashford
authors.forename: Emma
authors.initials: E
authors.lastname: Gayton
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hindmarsh
authors.forename: Julian P H
authors.initials: JP
authors.lastname: Shield
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Crowne
authors.forename: David
authors.initials: D
authors.lastname: Barford
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.forename: Ines
authors.initials: I
authors.lastname: Barroso
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006963:Hyperphagia / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D005227:Fatty Acids; C482119:BRAF protein, human; C557409:KSR2 protein, human; C542241:KSR2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D005947:Glucose