Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression.
Małgorzata RydzaniczMałgorzata WachowskaErik C CookPaweł LisowskiBożena KuźniewskaKrystyna SzymańskaSebastian DieckeAlessandro PrigioneKrzysztof SzczalubaAleksandra SzybińskaAgnieszka KoppoluVictor Murcia PienkowskiJoanna KosińskaMałgorzata WiwegerGrażyna KostrzewaMałgorzata BrzozowskaDorota Domańska-PakiełaElżbieta JurkiewiczPiotr StawińskiAgnieszka GromadkaPiotr ZielenkiewiczUrszula DemkowMagdalena DziembowskaJacek KuźnickiTrevor P CreamerRafał PłoskiPublished in: European journal of human genetics : EJHG (2018)
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.
Keyphrases
- early onset
- protein kinase
- late onset
- induced apoptosis
- wild type
- binding protein
- cell cycle arrest
- protein protein
- amino acid
- signaling pathway
- case report
- transcription factor
- small molecule
- gene expression
- oxidative stress
- epstein barr virus
- cell proliferation
- diffuse large b cell lymphoma
- south africa
- microbial community
- copy number
- blood brain barrier
- subarachnoid hemorrhage
- anaerobic digestion
- antibiotic resistance genes