Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression

Item Type:	Article
Title:	Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression
Creators Name:	Rydzanicz, M. and Wachowska, M. and Cook, E.C. and Lisowski, P. and Kuźniewska, B. and Szymańska, K. and Diecke, S. and Prigione, A. and Szczałuba, K. and Szybińska, A. and Koppolu, A. and Murcia Pienkowski, V. and Kosińska, J. and Wiweger, M. and Kostrzewa, G. and Brzozowska, M. and Domańska-Pakieła, D. and Jurkiewicz, E. and Stawiński, P. and Gromadka, A. and Zielenkiewicz, P. and Demkow, U. and Dziembowska, M. and Kuźnicki, J. and Creamer, T.P. and Płoski, R.
Abstract:	PPP3CA encodes calmodulin-binding catalytic subunit of calcineurin, a ubiquitously expressed calcium/calmodulin-regulated protein phosphatase. Recently de novo PPP3CA variants were reported as a cause of disease in 12 subjects presenting with epileptic encephalopathy and dysmorphic features. We describe a boy with similar phenotype and severe early onset epileptic encephalopathy in whom a novel de novo c.1324C>T (p.(Gln442Ter)) PPP3CA variant was found by whole exome sequencing. Western blot experiments in patient's cells (EBV transformed lymphocytes and neuronal cells derived through reprogramming) indicate that despite normal mRNA abundance the protein expression level is strongly reduced both for the mutated and wild-type protein. By in vitro studies with recombinant protein expressed in E. coli we show that c.1324C>T (p.(Gln442Ter)) results in constitutive activation of the enzyme. Our results confirm the role of PPP3CA defects in pathogenesis of a distinct neurodevelopmental disorder including severe epilepsy and dysmorphism and provide further functional clues regarding the pathogenic mechanism.
Keywords:	Calcineurin, Craniofacial Abnormalities, Cultured Cells, Down-Regulation, Epilepsy, Missense Mutation, Phenotype, Syndrome
Source:	European Journal of Human Genetics
ISSN:	1018-4813
Publisher:	Nature Publishing Group
Volume:	27
Number:	1
Page Range:	61-69
Date:	January 2019
Official Publication:	https://doi.org/10.1038/s41431-018-0254-8
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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