Evidence map›Paper›PMID 30595372›Full record

ArticleAmerican journal of human genetics2019

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 and 27 more

Erratum issuedOpen access · bronzeAbstract read
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In one paragraph

Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 27 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed, 1 pooled it
3.6field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

27 citing papers in PubMed, 1 synthesis or guideline pooled it, 59 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

37 authors at 19 institutions in 6 countries.

Sara ReynhoutLaboratory 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.
Sandra JansenDepartment of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Dorien HaesenLaboratory 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.
Siska van BelleLaboratory 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.
Sonja A de MunnikDepartment of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Ernie M H F BongersDepartment of Human Genetics, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Jolanda H SchievingDepartment of Neurology, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Carlo MarcelisDepartment of Human Genetics, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Jeanne AmielLaboratory 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.
Marlène RioService de Génétique, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
Heather MclaughlinGeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Roger LaddaPenn State Hershey Children's Hospital, Hershey, PA 17033, USA.
Susan SellPenn State Hershey Children's Hospital, Hershey, PA 17033, USA.
Marjolein KriekDepartment of Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
Cacha M P C D Peeters-ScholteDepartment of Neurology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
Paulien A TerhalDepartment of Genetics, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.
Koen L van GassenDepartment of Genetics, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.
Nienke VerbeekDepartment of Genetics, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.
Sonja HenryBiochemical Genetics Clinic, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.
Jessica Scott SchwoererBiochemical Genetics Clinic, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.
Saleem MalikComprehensive Epilepsy Program, Jane and John Justin Neuroscience Center, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
Nicole RevencuCentre de Génétique Humaine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10-1200, Brussels, Belgium.
Carlos R FerreiraOffice of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Ellen MacnamaraOffice 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.
Hilde M H BraakmanDepartment of Neurology, Academic Center for Epileptology, Kempenhaeghe & Maastricht UMC+, Sterkelseweg 65, 5591 VE Heeze, the Netherlands.
Elise BrimbleDepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Maura R Z RuzhnikovDepartment 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.
Matias WagnerInstitute 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.
Philip HarrerInstitute of Neurogenomics, Helmholtz Zentrum München, 85764 Munich, Germany.
Dagmar WieczorekInstitute of Human Genetics, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany; Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
Alma KuechlerInstitut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
Barak TzipermanPediatric Neurology Unit, Sheba Medical Center, 52621 Ramat Gan, Israel.
Ortal BarelGenomic Unit, Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel Hashomer, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel Hashomer, Israel.
Bert B A de VriesDepartment of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Christopher T GordonLaboratory of Embryology and Genetics of Human Malformations, Paris Descartes University, Sorbonne Paris Cité University and INSERM U1163, Institut Imagine, 75015 Paris, France.
Veerle JanssensLaboratory 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.
Lisenka E L M VissersDepartment 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.
Radboud University Nijmegen · NLVIB-KU Leuven Center for Brain & Disease Research · BEUtrecht University · NLDélégation Paris 5 · FRLeiden University Medical Center · NLNational Institutes of Health · USPenn State Milton S. Hershey Medical Center · USSheba Medical Center · ILUniversity of Wisconsin–Madison · USCliniques Universitaires Saint-Luc · BECook Children's Medical Center · USDüsseldorf University Hospital · DEEssen University Hospital · DEHelmholtz Zentrum München · DEHôpital Necker-Enfants Malades · FRMaastricht University Medical Centre · NLStanford Medicine · USStanford University · USTUM Klinikum · DE

Funding

Wellcome Trust
6 · The paper itself

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.

Indexed as

MutationAdolescentChildChild, PreschoolDNA Mutational AnalysisFemaleHaploinsufficiencyHEK293 CellsHumansIntellectual DisabilityMaleProtein BindingProtein Phosphatase 2Protein SubunitsSyndromePPP2CA protein, humanProtein Phosphatase 2Protein Subunitsde novo mutationepilepsyintellectual disabilityPP2APP2A-related neurodevelopmental disordersPPP2CAsyndrome

Identifiers

PMID30595372
PMCPMC6323609
OpenAlexW2907720528

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.