TY - JOUR
T1 - De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders
AU - Reynhout, Sara
AU - Jansen, Sandra
AU - Haesen, Dorien
AU - van Belle, Siska
AU - de Munnik, Sonja A.
AU - Bongers, Ernie M. H. F.
AU - Schieving, Jolanda H.
AU - Marcelis, Carlo
AU - Amiel, Jeanne
AU - Rio, Marlène
AU - Mclaughlin, Heather
AU - Ladda, Roger
AU - Sell, Susan
AU - Kriek, Marjolein
AU - Peeters-Scholte, Cacha M. P. C. D.
AU - Terhal, Paulien A.
AU - van Gassen, Koen L.
AU - Verbeek, Nienke
AU - Henry, Sonja
AU - Scott Schwoerer, Jessica
AU - Malik, Saleem
AU - Revencu, Nicole
AU - Ferreira, Carlos R.
AU - Macnamara, Ellen
AU - Braakman, Hilde M. H.
AU - Brimble, Elise
AU - Ruznikov, Maura R. Z.
AU - Wagner, Matias
AU - Harrer, Philip
AU - Wieczorek, Dagmar
AU - Kuechler, Alma
AU - Tziperman, Barak
AU - Barel, Ortal
AU - de Vries, Bert B. A.
AU - Gordon, Christopher T.
AU - Janssens, Veerle
AU - Vissers, Lisenka E. L. M.
PY - 2019/1/3
Y1 - 2019/1/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85059497872
UR - https://www.ncbi.nlm.nih.gov/pubmed/30595372
U2 - 10.1016/j.ajhg.2018.12.002
DO - 10.1016/j.ajhg.2018.12.002
M3 - Article
C2 - 30595372
SN - 0002-9297
VL - 104
SP - 139
EP - 156
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -