%0 Journal Article
%T De Novo Mutations Affecting the Catalytic C¦Á Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders
%A Alma Kuechler
%A Barak Tziperman
%A Bert B.A. de Vries
%A Cacha M.P.C.D. Peeters-Scholte
%A Carlo Marcelis
%A Carlos R. Ferreira
%A Christopher T. Gordon
%A Dagmar Wieczorek
%A Dorien Haesen
%A Elise Brimble
%A Ellen Macnamara
%A Ernie M.H.F. Bongers
%A Heather Mclaughlin
%A Hilde M.H. Braakman
%A Jeanne Amiel
%A Jessica Scott Schwoerer
%A Jolanda H. Schieving
%A Koen L. van Gassen
%A Marjolein Kriek
%A Marl¨¨ne Rio
%A Matias Wagner
%A Maura R.Z. Ruznikov
%A Nicole Revencu
%A Nienke Verbeek
%A Ortal Barel
%A Paulien A. Terhal
%A Philip Harrer
%A Roger Ladda
%A Saleem Malik
%A Sandra Jansen
%A Sara Reynhout
%A Siska van Belle
%A Sonja A. de Munnik
%A Sonja Henry
%A Susan Sell
%A Veerle Janssens
%J Archive of "American Journal of Human Genetics".
%D 2019
%R 10.1016/j.ajhg.2018.12.002
%X 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 C¦Á 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(¦Ä) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes
%K PPP2CA
%K PP2A
%K intellectual disability
%K syndrome
%K de novo mutation
%K epilepsy
%K PP2A-related neurodevelopmental disorders
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323609/