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

Sara Reynhout; Sandra Jansen; Dorien Haesen; Siska van Belle; Sonja A de Munnik; Ernie M H F Bongers; Jolanda H Schieving; Carlo Marcelis; Jeanne Amiel; Marlène Rio; Heather Mclaughlin; Roger Ladda; Susan Sell; Marjolein Kriek; Cacha M P C D Peeters-Scholte; Paulien A Terhal; Koen L van Gassen; Nienke Verbeek; Sonja Henry; Jessica Scott Schwoerer; Saleem Malik; Nicole Revencu; Carlos R Ferreira; Ellen Macnamara; Hilde M H Braakman; Elise Brimble; Maura R Z Ruzhnikov; Matias Wagner; Philip Harrer; Dagmar Wieczorek; Alma Kuechler; Barak Tziperman; Ortal Barel; Bert B A de Vries; Christopher T Gordon; Veerle Janssens; Lisenka E L M Vissers

doi:10.1016/j.ajhg.2018.12.002

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. Epub 2018 Dec 27.

Authors

Sara Reynhout¹, Sandra Jansen², Dorien Haesen¹, Siska van Belle¹, Sonja A de Munnik², Ernie M H F Bongers³, Jolanda H Schieving⁴, Carlo Marcelis³, Jeanne Amiel⁵, Marlène Rio⁶, Heather Mclaughlin⁷, Roger Ladda⁸, Susan Sell⁸, Marjolein Kriek⁹, Cacha M P C D Peeters-Scholte¹⁰, Paulien A Terhal¹¹, Koen L van Gassen¹¹, Nienke Verbeek¹¹, Sonja Henry¹², Jessica Scott Schwoerer¹², Saleem Malik¹³, Nicole Revencu¹⁴, Carlos R Ferreira¹⁵, Ellen Macnamara¹⁶, Hilde M H Braakman¹⁷, Elise Brimble¹⁸, Maura R Z Ruzhnikov¹⁹, Matias Wagner²⁰, Philip Harrer²¹, Dagmar Wieczorek²², Alma Kuechler²³, Barak Tziperman²⁴, Ortal Barel²⁵, Bert B A de Vries², Christopher T Gordon²⁶, Veerle Janssens²⁷, Lisenka E L M Vissers²⁸

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: veerle.janssens@kuleuven.be.
²⁸ Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address: lisenka.vissers@radboudumc.nl.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Child
Child, Preschool
DNA Mutational Analysis
Female
HEK293 Cells
Haploinsufficiency / genetics
Humans
Intellectual Disability / genetics*
Male
Mutation*
Protein Binding / genetics
Protein Phosphatase 2 / genetics*
Protein Subunits / chemistry
Protein Subunits / metabolism
Syndrome

Substances

Protein Subunits
PPP2CA protein, human
Protein Phosphatase 2

Grants and funding

Wellcome Trust/United Kingdom