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)
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
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
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 104, Heft: 1, Seiten: 139-156
Verlag Elsevier ; Cell Press
Verlagsort New York, NY