De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders

  • Am J Hum Genet. 2019 Jan 3;104(1):139-156. doi: 10.1016/j.ajhg.2018.12.002.
Sara Reynhout  1 ,  Sandra Jansen  2 ,  Dorien Haesen  1 ,  Siska van Belle  1 ,  Sonja A de Munnik  2 ,  Ernie M H F Bongers  3 ,  Jolanda H Schieving  4 ,  Carlo Marcelis  3 ,  Jeanne Amiel  5 ,  Marlène Rio  6 ,  Heather Mclaughlin  7 ,  Roger Ladda  8 ,  Susan Sell  8 ,  Marjolein Kriek  9 ,  Cacha M P C D Peeters-Scholte  10 ,  Paulien A Terhal  11 ,  Koen L van Gassen  11 ,  Nienke Verbeek  11 ,  Sonja Henry  12 ,  Jessica Scott Schwoerer  12 ,  Saleem Malik  13 ,  Nicole Revencu  14 ,  Carlos R Ferreira  15 ,  Ellen Macnamara  16 ,  Hilde M H Braakman  17 ,  Elise Brimble  18 ,  Maura R Z Ruzhnikov  19 ,  Matias Wagner  20 ,  Philip Harrer  21 ,  Dagmar Wieczorek  22 ,  Alma Kuechler  23 ,  Barak Tziperman  24 ,  Ortal Barel  25 ,  Bert B A de Vries  2 ,  Christopher T Gordon  26 ,  Veerle Janssens  27 ,  Lisenka E L M Vissers  28
Affiliations
  • 1. Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), 3000 Leuven, Belgium; Leuven Brain Institute, PO Box 901, 3000 Leuven, Belgium.
  • 2. Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
  • 3. Department of Human Genetics, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
  • 4. Department of Neurology, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
  • 5. Laboratory of Embryology and Genetics of Human Malformations, Paris Descartes University, Sorbonne Paris Cité University and INSERM U1163, Institut Imagine, 75015 Paris, France; Service de Génétique, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
  • 6. Service de Génétique, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
  • 7. GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 8. Penn State Hershey Children's Hospital, Hershey, PA 17033, USA.
  • 9. Department of Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
  • 10. Department of Neurology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
  • 11. Department of Genetics, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.
  • 12. Biochemical Genetics Clinic, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.
  • 13. Comprehensive Epilepsy Program, Jane and John Justin Neuroscience Center, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
  • 14. Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10-1200, Brussels, Belgium.
  • 15. Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 16. Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 17. Department of Neurology, Academic Center for Epileptology, Kempenhaeghe & Maastricht UMC+, Sterkelseweg 65, 5591 VE Heeze, the Netherlands.
  • 18. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 19. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA; Department of Pediatrics, Division of Medical Genetics, Stanford Medicine, Stanford, CA 94305, USA.
  • 20. Institute of Human Genetics, Helmholtz Zentrum München, 85764 Munich, Germany; Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Munich, Germany.
  • 21. Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Munich, Germany.
  • 22. Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany; Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
  • 23. Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
  • 24. Pediatric Neurology Unit, Sheba Medical Center, 52621 Ramat Gan, Israel.
  • 25. Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel Hashomer, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel Hashomer, Israel.
  • 26. Laboratory of Embryology and Genetics of Human Malformations, Paris Descartes University, Sorbonne Paris Cité University and INSERM U1163, Institut Imagine, 75015 Paris, France.
  • 27. Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), 3000 Leuven, Belgium; Leuven Brain Institute, PO Box 901, 3000 Leuven, Belgium. Electronic address: [email protected].
  • 28. Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address: [email protected].
PMID: 30595372 DOI: 10.1016/j.ajhg.2018.12.002
Abstract

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate Neuronal Signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), Epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired Phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

Keywords
PP2A; PP2A-related neurodevelopmental disorders; PPP2CA; de novo mutation; epilepsy; intellectual disability; syndrome.