Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression
| Autor: | Alessandro Prigione, Małgorzata Rydzanicz, Dorota Domańska-Pakieła, Urszula Demkow, Piotr Stawiński, Malgorzata Wiweger, Elżbieta Jurkiewicz, Erik C. Cook, Krystyna Szymańska, Trevor P. Creamer, Grażyna Kostrzewa, Małgorzata Brzozowska, Pawel Lisowski, Bożena Kuźniewska, Magdalena Dziembowska, Aleksandra Szybinska, Sebastian Diecke, Malgorzata Wachowska, Joanna Kosińska, Krzysztof Szczałuba, Rafał Płoski, Victor Murcia Pienkowski, Agnieszka Koppolu, Agnieszka Gromadka, Piotr Zielenkiewicz, Jacek Kuźnicki |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
Protein subunit Phosphatase Mutation Missense Down-Regulation Biology medicine.disease_cause Article Craniofacial Abnormalities 03 medical and health sciences Enzyme activator Downregulation and upregulation Western blot Genetics medicine Humans Child Genetics (clinical) Exome sequencing Cells Cultured 0303 health sciences Mutation Epilepsy medicine.diagnostic_test Calcineurin 030305 genetics & heredity Syndrome Molecular biology Phenotype |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|