De Novo Mutations Affecting the Catalytic Calpha Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders
| العنوان: | De Novo Mutations Affecting the Catalytic Calpha Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders |
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| المؤلفون: | Ellen Macnamara, Marlène Rio, Nicole Revencu, Saleem Malik, Siska Van Belle, Maura R.Z. Ruzhnikov, Jolanda H. Schieving, Lisenka E.L.M. Vissers, Barak Tziperman, Hilde M.H. Braakman, Alma Kuechler, Susan Sell, Philip Harrer, Ernie M.H.F. Bongers, Marjolein Kriek, Dagmar Wieczorek, Bert B.A. de Vries, Christopher T. Gordon, Jeanne Amiel, Matias Wagner, Dorien Haesen, Roger L. Ladda, Koen L.I. van Gassen, Elise Brimble, Sandra Jansen, Sonja Henry, Carlo Marcelis, Paulien A Terhal, Nienke E. Verbeek, Ortal Barel, Sara Reynhout, Carlos Ferreira, Jessica Scott Schwoerer, Veerle Janssens, Heather M. McLaughlin, Sonja A. de Munnik, Cacha M.P.C.D. Peeters-Scholte |
| المساهمون: | UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - SSS/IREC/SLUC - Pôle St.-Luc |
| المصدر: | American Journal of Human Genetics, 104, 1, pp. 139-156 American journal of human genetics, Vol. 104, no. 1, p. 139-156 (2019) American Journal of Human Genetics, 104(1), 139. Cell Press American Journal of Human Genetics, 104, 139-156 Am. J. Hum. Genet. 104, 139-156 (2019) American Journal of Human Genetics, 104(1), 139-156 |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, DNA Mutational Analysis, Medizin, Haploinsufficiency, 0302 clinical medicine, De Novo Mutation, Epilepsy, Intellectual Disability, Pp2a, Pp2a-related Neurodevelopmental Disorders, Ppp2ca, Syndrome, Intellectual disability, Gene duplication, Missense mutation, Genetics(clinical), Protein Phosphatase 2, Child, Genetics (clinical), Genetics, 0303 health sciences, 030302 biochemistry & molecular biology, syndrome, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hypotonia, PP2A, intellectual disability, Child, Preschool, Female, medicine.symptom, Protein Binding, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adolescent, Protein subunit, Nonsense mutation, Biology, Article, PP2A-related neurodevelopmental disorders, Frameshift mutation, 03 medical and health sciences, medicine, Humans, Gene, De novo mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Correction, medicine.disease, Human genetics, PPP2CA, de novo mutation, Protein Subunits, HEK293 Cells, 030104 developmental biology, Mutation, epilepsy, 030217 neurology & neurosurgery |
| الوصف: | 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. ispartof: American Journal Of Human Genetics vol:104 issue:1 pages:139-156 ispartof: location:United States status: published |
| وصف الملف: | image/pdf; application/pdf; Print-Electronic |
| تدمد: | 0002-9297 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bebe5a429039fe84e3b036fb1114bb20 https://hdl.handle.net/2066/202645 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....bebe5a429039fe84e3b036fb1114bb20 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00029297 |
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