TY - JOUR
T1 - Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression
AU - Rydzanicz, Małgorzata
AU - Wachowska, Małgorzata
AU - Cook, Erik C.
AU - Lisowski, Paweł
AU - Kuźniewska, Bożena
AU - Szymańska, Krystyna
AU - Diecke, Sebastian
AU - Prigione, Alessandro
AU - Szczałuba, Krzysztof
AU - Szybińska, Aleksandra
AU - Koppolu, Agnieszka
AU - Murcia Pienkowski, Victor
AU - Kosińska, Joanna
AU - Wiweger, Małgorzata
AU - Kostrzewa, Grażyna
AU - Brzozowska, Małgorzata
AU - Domańska-Pakieła, Dorota
AU - Jurkiewicz, Elżbieta
AU - Stawiński, Piotr
AU - Gromadka, Agnieszka
AU - Zielenkiewicz, Piotr
AU - Demkow, Urszula
AU - Dziembowska, Magdalena
AU - Kuźnicki, Jacek
AU - Creamer, Trevor P.
AU - Płoski, Rafał
N1 - Publisher Copyright:
© 2018, European Society of Human Genetics.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41431-018-0254-8
DO - 10.1038/s41431-018-0254-8
M3 - Article
C2 - 30254215
AN - SCOPUS:85053925674
SN - 1018-4813
VL - 27
SP - 61
EP - 69
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -