TY - JOUR
T1 - Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth
AU - Loveday, Chey
AU - Tatton-Brown, Katrina
AU - Clarke, Matthew
AU - Westwood, Isaac
AU - Renwick, Anthony
AU - Ramsay, Emma
AU - Nemeth, Andrea
AU - Campbell, Jennifer
AU - Joss, Shelagh
AU - Gardner, McKinlay
AU - Zachariou, Anna
AU - Elliott, Anna
AU - Ruark, Elise
AU - van Montfort, Rob
AU - Rahman, Nazneen
AU - AUTHOR GROUP
AU - Ahmed, M.
AU - Anderson, K.
AU - Archer, H.
AU - Armstrong, R.
AU - Baralle, D.
AU - Barnicoat, A.
AU - Barrow, M.
AU - Barwell, J.
AU - Beales, P.
AU - Becker, K.
AU - Berg, J.
AU - Bernhard, B.
AU - Bhal, S.
AU - Birch, J.
AU - Bitner, M.
AU - Blair, E.
AU - Blyth, M.
AU - Bradley, L.
AU - Brady, A.
AU - Brice, G.
AU - Brueton, L.
AU - Burke, A.
AU - Burn, J.
AU - Campbell, J.
AU - Canham, N.
AU - Castle, B.
AU - Chandler, K.
AU - Chandrasena, R.
AU - Chu, C.
AU - Cilliers, D.
AU - Clarke, A.
AU - Clayton-Smith, J.
AU - Clowes, V.
AU - Cole, T.
AU - Hennekam, R.
PY - 2015
Y1 - 2015
N2 - 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 x 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 x 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
AB - 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 x 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 x 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
U2 - https://doi.org/10.1093/hmg/ddv182
DO - https://doi.org/10.1093/hmg/ddv182
M3 - Article
C2 - 25972378
SN - 0964-6906
VL - 24
SP - 4775
EP - 4779
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 17
ER -