title: Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth.
abstract: Overgrowth syndromes comprise a group of heterogeneous disorders characterised by excessive growth parameters, often in association with intellectual disability. To identify new causes of human overgrowth, we have been undertaking trio-based exome sequencing studies in overgrowth patients and their unaffected parents. Prioritisation of functionally relevant genes with multiple unique de novo mutations revealed four mutations in protein phosphatase 2A (PP2A) regulatory subunit B family genes protein phosphatase 2, regulatory Subunit B', beta (PPP2R5B); protein phosphatase 2, regulatory Subunit B', gamma (PPP2R5C); and protein phosphatase 2, regulatory Subunit B', delta (PPP2R5D). This observation in 3 related genes in 111 individuals with a similar phenotype is greatly in excess of the expected number, as determined from gene-specific de novo mutation rates (P = 1.43 × 10(-10)). Analysis of exome-sequencing data from a follow-up series of overgrowth probands identified a further pathogenic mutation, bringing the total number of affected individuals to 5. Heterozygotes shared similar phenotypic features including increased height, increased head circumference and intellectual disability. The mutations clustered within a region of nine amino acid residues in the aligned protein sequences (P = 1.6 × 10(-5)). We mapped the mutations onto the crystal structure of the PP2A holoenzyme complex to predict their molecular and functional consequences. These studies suggest that the mutations may affect substrate binding, thus perturbing the ability of PP2A to dephosphorylate particular protein substrates. PP2A is a major negative regulator of v-akt murine thymoma viral oncogene homolog 1 (AKT). Thus, our data further expand the list of genes encoding components of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signalling cascade that are disrupted in human overgrowth conditions.
authors.affiliation: Division of Genetics and Epidemiology.
authors.forename: Chey
authors.initials: C
authors.lastname: Loveday
authors.affiliation: Division of Genetics and Epidemiology, Medical Genetics Unit, St George's University of London, London, UK, Cancer Genetics Unit, Royal Marsden Hospital, London, UK.
authors.forename: Katrina
authors.initials: K
authors.lastname: Tatton-Brown
authors.affiliation: Division of Genetics and Epidemiology.
authors.forename: Matthew
authors.initials: M
authors.lastname: Clarke
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, Institute of Cancer Research, London, UK.
authors.forename: Isaac
authors.initials: I
authors.lastname: Westwood
authors.affiliation: Division of Genetics and Epidemiology.
authors.forename: Anthony
authors.initials: A
authors.lastname: Renwick
authors.affiliation: Division of Genetics and Epidemiology.
authors.forename: Emma
authors.initials: E
authors.lastname: Ramsay
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nemeth
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Campbell
authors.affiliation: West of Scotland Genetic Services, Southern General Hospital, Scotland, UK, Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK and.
authors.forename: Shelagh
authors.initials: S
authors.lastname: Joss
authors.affiliation: Genetic Health Service New Zealand, Wellington Hospital, Wellington, NZ.
authors.forename: McKinlay
authors.initials: M
authors.lastname: Gardner
authors.affiliation: Division of Genetics and Epidemiology.
authors.forename: Anna
authors.initials: A
authors.lastname: Zachariou
authors.affiliation: Division of Genetics and Epidemiology.
authors.forename: Anna
authors.initials: A
authors.lastname: Elliott
authors.affiliation: Division of Genetics and Epidemiology.
authors.forename: Elise
authors.initials: E
authors.lastname: Ruark
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, Institute of Cancer Research, London, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: van Montfort
authors.affiliation: Division of Genetics and Epidemiology, Cancer Genetics Unit, Royal Marsden Hospital, London, UK, rahmanlab@icr.ac.uk.
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D059472:Exome; D056726:Genetic Association Studies; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C525691:PPP2R5D protein, human; C503493:PPP2R5B protein, human; C503981:PPP2R5C protein, human; D054648:Protein Phosphatase 2