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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)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 104, Heft: 1, Seiten: 139-156 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)