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

Autor: Rydzanicz M; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Wachowska M; Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland., Cook EC; Center for Structural Biology and Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, USA., Lisowski P; Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzębiec, Poland.; Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany., Kuźniewska B; Centre of New Technologies, University of Warsaw, Warsaw, Poland., Szymańska K; Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland., Diecke S; Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany., Prigione A; Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany., Szczałuba K; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Szybińska A; International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland., Koppolu A; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland., Murcia Pienkowski V; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland., Kosińska J; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Wiweger M; International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland., Kostrzewa G; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Brzozowska M; Department of Forensic Medicine, Medical University of Warsaw, Warsaw, Poland., Domańska-Pakieła D; Department of Child Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland., Jurkiewicz E; Department of Diagnostic Imaging, The Children's Memorial Health Institute, Warsaw, Poland., Stawiński P; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Gromadka A; Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland., Zielenkiewicz P; Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland., Demkow U; Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland., Dziembowska M; Centre of New Technologies, University of Warsaw, Warsaw, Poland., Kuźnicki J; International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland., Creamer TP; Center for Structural Biology and Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, USA., Płoski R; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland. rploski@wp.pl.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2019 Jan; Vol. 27 (1), pp. 61-69. Date of Electronic Publication: 2018 Sep 25.
DOI: 10.1038/s41431-018-0254-8
Abstrakt: 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: MEDLINE
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