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Reynhout, S.* ; Jansen, S.* ; Haesen, D.* ; van Belle, S.* ; de Munnik, S.A.* ; Bongers, E.M.H.F.* ; Schieving, J.H.* ; Marcelis, C.L.* ; Amiel, J.* ; Rio, M.* ; Mclaughlin, H.* ; Ladda, R.* ; Sell, S.* ; Kriek, M.* ; Peeters-Scholte, C.M.P.C.D.* ; Terhal, P.A.* ; van Gassen, K.L.* ; Verbeek, N.* ; Henry, S.* ; Scott Schwoerer, J.* ; Malik, S.* ; Revencu, N.* ; Ferreira, C.R.* ; Macnamara, E.* ; Braakman, H.M.H.* ; Brimble, E.* ; Ruznikov, M.R.Z.* ; Wagner, M. ; Harrer, P- ; Wieczorek, D.* ; Kuechler, A.* ; Tziperman, B.* ; Barel, O.* ; de Vries, B.B.A.* ; Gordon, C.T.* ; Janssens, V.* ; Vissers, L.E.L.M.*

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. 104, 139-156 (2019)
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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 sub-units 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 C alpha, 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-1356(delta) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.
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Publication type Article: Journal article
Document type Scientific Article
Keywords De Novo Mutation ; Epilepsy ; Intellectual Disability ; Pp2a ; Pp2a-related Neurodevelopmental Disorders ; Ppp2ca ; Syndrome; Protein Phosphatase 2a; Alternatively Spliced Isoform; Structural Basis; Regulatory Subunit; Gene; Haploinsufficiency; Methylesterase; Identification; Inactivation; Terminus
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Quellenangaben Volume: 104, Issue: 1, Pages: 139-156 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed