B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.

Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3β, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.

[1]  Tomas W. Fitzgerald,et al.  Large-scale discovery of novel genetic causes of developmental disorders , 2014, Nature.

[2]  L. Vissers,et al.  Genome sequencing identifies major causes of severe intellectual disability , 2014, Nature.

[3]  P. Nordlund,et al.  Structural and Biochemical Characterization of Human PR70 in Isolation and in Complex with the Scaffolding Subunit of Protein Phosphatase 2A , 2014, PloS one.

[4]  Jason J Burbank,et al.  Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. , 2014, The Journal of clinical investigation.

[5]  F. Guo,et al.  Mechanisms of the Scaffold Subunit in Facilitating Protein Phosphatase 2A Methylation , 2014, PloS one.

[6]  C. Lohmann,et al.  The developmental stages of synaptic plasticity , 2014, The Journal of physiology.

[7]  Caroline F. Wright,et al.  DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation , 2013, Nucleic Acids Res..

[8]  Jason J Burbank,et al.  Phenothiazines induce PP 2 A-mediated apoptosis in T cell acute lymphoblastic leukemia , 2014 .

[9]  G. McVean,et al.  Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline , 2013, Proceedings of the National Academy of Sciences.

[10]  F. Guo,et al.  Structure of the Ca2+-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation , 2013, Cell Research.

[11]  C. Hultman,et al.  "Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders. , 2013, The American journal of psychiatry.

[12]  D. Perrotti,et al.  Protein phosphatase 2A: a target for anticancer therapy. , 2013, The Lancet. Oncology.

[13]  J. Rivière,et al.  Megalencephaly Syndromes and Activating Mutations in the PI3K‐AKT Pathway: MPPH and MCAP , 2013, American journal of medical genetics. Part C, Seminars in medical genetics.

[14]  V. Janssens,et al.  The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity , 2013, The FEBS journal.

[15]  F. Guo,et al.  Structure of the Ca 2 +-dependent PP 2 A heterotrimer and insights into Cdc 6 dephosphorylation , 2013 .

[16]  B. V. van Bon,et al.  Diagnostic exome sequencing in persons with severe intellectual disability. , 2012, The New England journal of medicine.

[17]  R. Dolmetsch,et al.  Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy , 2012, The EMBO journal.

[18]  V. Janssens,et al.  The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells. , 2012, Current molecular medicine.

[19]  G. Walter,et al.  Mouse model for probing tumor suppressor activity of protein phosphatase 2A in diverse signaling pathways , 2012, Cell cycle.

[20]  R. Eisenman,et al.  Regulation of c-Myc Protein Abundance by a Protein Phosphatase 2A-Glycogen Synthase Kinase 3β-Negative Feedback Pathway. , 2012, Genes & cancer.

[21]  P. Greengard,et al.  Protein Kinase C-Dependent Dephosphorylation of Tyrosine Hydroxylase Requires the B56δ Heterotrimeric Form of Protein Phosphatase 2A , 2011, PloS one.

[22]  I. Landrieu,et al.  Mice lacking phosphatase PP2A subunit PR61/B’δ (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β , 2011, Proceedings of the National Academy of Sciences.

[23]  A. Mes-Masson,et al.  Subtype‐specific mutation of PPP2R1A in endometrial and ovarian carcinomas , 2011, The Journal of pathology.

[24]  V. Velculescu,et al.  Somatic mutations of PPP2R1A in ovarian and uterine carcinomas. , 2011, The American journal of pathology.

[25]  C. Phiel,et al.  Functions of B56-containing PP2As in major developmental and cancer signaling pathways. , 2010, Life sciences.

[26]  Volker Brinkmann,et al.  Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis , 2010, Nature Reviews Drug Discovery.

[27]  Daniel Rios,et al.  Bioinformatics Applications Note Databases and Ontologies Deriving the Consequences of Genomic Variants with the Ensembl Api and Snp Effect Predictor , 2022 .

[28]  Jung-Hyuck Ahn,et al.  Phosphorylation on the PPP2R5D B regulatory subunit modulates the biochemical properties of protein phosphatase 2A. , 2010, BMB reports.

[29]  A. Nairn,et al.  cAMP-stimulated Protein Phosphatase 2A Activity Associated with Muscle A Kinase-anchoring Protein (mAKAP) Signaling Complexes Inhibits the Phosphorylation and Activity of the cAMP-specific Phosphodiesterase PDE4D3* , 2010, The Journal of Biological Chemistry.

[30]  G. Francis,et al.  Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis , 2010, Nature Reviews Drug Discovery.

[31]  Jung-Hyuck Ahn,et al.  Phosphorylation on the PPP 2 R 5 D B regulatory subunit modulates the biochemical properties of protein phosphatase 2 A , 2010 .

[32]  Kim Nasmyth,et al.  Structure and function of the PP2A-shugoshin interaction. , 2009, Molecular cell.

[33]  Brian Raught,et al.  A PP2A Phosphatase High Density Interaction Network Identifies a Novel Striatin-interacting Phosphatase and Kinase Complex Linked to the Cerebral Cavernous Malformation 3 (CCM3) Protein*S , 2009, Molecular & Cellular Proteomics.

[34]  Yigong Shi,et al.  Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation. , 2008, Molecular cell.

[35]  Paul Greengard,et al.  A phosphatase cascade by which rewarding stimuli control nucleosomal response , 2008, Nature.

[36]  V. Janssens,et al.  Selection of Protein Phosphatase 2A Regulatory Subunits Is Mediated by the C Terminus of the Catalytic Subunit* , 2007, Journal of Biological Chemistry.

[37]  Angus C Nairn,et al.  The B″/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A , 2007, Proceedings of the National Academy of Sciences.

[38]  E. Ogris,et al.  Generation of Active Protein Phosphatase 2A Is Coupled to Holoenzyme Assembly , 2007, PLoS biology.

[39]  Angus C Nairn,et al.  Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56δ subunit , 2007, Proceedings of the National Academy of Sciences.

[40]  Wenqing Xu,et al.  Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme , 2007, Nature.

[41]  Yigong Shi,et al.  Structure of the Protein Phosphatase 2A Holoenzyme , 2006, Cell.

[42]  John D. Scott,et al.  Spatial restriction of PDK1 activation cascades by anchoring to mAKAPalpha. , 2005, Molecular cell.

[43]  W. Hahn,et al.  Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity. , 2005, Cancer research.

[44]  Lisa L Gomez,et al.  Critical Role for Protein Phosphatase 2A Heterotrimers in Mammalian Cell Survival* , 2004, Journal of Biological Chemistry.

[45]  J. Vermeesch,et al.  Genomic organisation, chromosomal localisation tissue distribution and developmental regulation of the PR61/B' regulatory subunits of protein phosphatase 2A in mice. , 2004, Journal of molecular biology.

[46]  V. Centonze,et al.  PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation. , 2003, Molecular cell.

[47]  E. Ogris,et al.  A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo. , 2003, Genes & development.

[48]  V. Janssens,et al.  Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. , 2001, The Biochemical journal.

[49]  Brian A. Hemmings,et al.  The Structure of the Protein Phosphatase 2A PR65/A Subunit Reveals the Conformation of Its 15 Tandemly Repeated HEAT Motifs , 1999, Cell.

[50]  D. Virshup,et al.  The B56 Family of Protein Phosphatase 2A (PP2A) Regulatory Subunits Encodes Differentiation-induced Phosphoproteins That Target PP2A to Both Nucleus and Cytoplasm* , 1996, The Journal of Biological Chemistry.