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

Małgorzata Rydzanicz, Małgorzata Wachowska, Erik C. Cook, Paweł Lisowski, Bożena Kuźniewska, Krystyna Szymańska, Sebastian Diecke, Alessandro Prigione, Krzysztof Szczałuba, Aleksandra Szybińska, Agnieszka Koppolu, Victor Murcia Pienkowski, Joanna Kosińska, Małgorzata Wiweger, Grażyna Kostrzewa, Małgorzata Brzozowska, Dorota Domańska-Pakieła, Elżbieta Jurkiewicz, Piotr Stawiński, Agnieszka GromadkaPiotr Zielenkiewicz, Urszula Demkow, Magdalena Dziembowska, Jacek Kuźnicki, Trevor P. Creamer, Rafał Płoski

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish
Pages (from-to)61-69
Number of pages9
JournalEuropean Journal of Human Genetics
Issue number1
StatePublished - Jan 1 2019

Bibliographical note

Publisher Copyright:
© 2018, European Society of Human Genetics.

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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