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, Heather Mclaughlin, Roger Ladda, Susan Sell, Marjolein Kriek, Cacha M. P. C. D. Peeters-Scholte, Paulien A. Terhal, Koen L. van Gassen, Nienke Verbeek, Sonja Henry, Jessica Scott SchwoererSaleem Malik, Nicole Revencu, Carlos R. Ferreira, Ellen Macnamara, Hilde M. H. Braakman, Elise Brimble, Maura R. Z. Ruznikov, Matias Wagner, Philip Harrer, Dagmar Wieczorek, Alma Kuechler, Barak Tziperman, Ortal Barel, Bert B. A. de Vries, Christopher T. Gordon, Veerle Janssens, Lisenka E. L. M. Vissers

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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 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.
Original languageEnglish
Pages (from-to)139-156
JournalAmerican journal of human genetics
Issue number1
Publication statusPublished - 3 Jan 2019
Externally publishedYes

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