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Am J Hum Genet. 2019 Jan 3;104(1):139-156. doi: 10.1016/j.ajhg.2018.12.002. Epub 2018 Dec 27.

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

Author information

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

PMID:
30595372
PMCID:
PMC6323609
[Available on 2019-07-03]
DOI:
10.1016/j.ajhg.2018.12.002

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