Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype.

Autor:	Knierim E; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, NeuroCure Clinical Research Center, 10117 Berlin, Germany.; Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany., Vogt J; Department of Molecular and Translational Neuroscience, Institute of Anatomy II, Cluster of Excellence-Cellular Stress Response in Aging-Associated Diseases (CECAD), Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., Kintscher M; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Neuroscience Research Center, 10117 Berlin, Germany.; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany., Ponomarenko A; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Neuroscience Research Center, 10117 Berlin, Germany.; Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany., Baumgart J; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Institute of Neurophysiology, 10117 Berlin, Germany.; Translational Animal Research Center (TARC), University Medical Center Mainz, 55128 Mainz, Germany., Beed P; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Neuroscience Research Center, 10117 Berlin, Germany., Korotkova T; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Neuroscience Research Center, 10117 Berlin, Germany.; Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany., Trimbuch T; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Institute of Neurophysiology, 10117 Berlin, Germany., Panzer A; Pediatric Neurology, DRK Kliniken-Westend, 14050 Berlin, Germany., Steinlein OK; Institute of Human Genetics, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany., Stephani U; Department of Child and Adolescent Medicine II, University Medical Center of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany., Escayg A; Department of Human Genetics, Emory University, Atlanta, GA 30322, United States., Koko M; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany., Liu Y; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany., Lerche H; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany., Schmitz D; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, NeuroCure Clinical Research Center, 10117 Berlin, Germany.; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Neuroscience Research Center, 10117 Berlin, Germany.; Humboldt-Universität zu Berlin, Bernstein Center for Computational Neuroscience, 10115 Berlin, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany.; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Einstein Center for Neuroscience, 10117 Berlin, Germany., Nitsch R; Institute for Translational Neuroscience, Westfälische Wilhelms University, 48149 Münster, Germany., Schuelke M; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, NeuroCure Clinical Research Center, 10117 Berlin, Germany.; Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Jazyk:	angličtina
Zdroj:	Cerebral cortex (New York, N.Y. : 1991) [Cereb Cortex] 2023 Jun 08; Vol. 33 (12), pp. 7454-7467.
DOI:	10.1093/cercor/bhad051
Abstrakt:	The Phospholipid Phosphatase Related 4 gene (PLPPR4,  *607813) encodes the Plasticity-Related-Gene-1 (PRG-1) protein. This cerebral synaptic transmembrane-protein modulates cortical excitatory transmission on glutamatergic neurons. In mice, homozygous Prg-1 deficiency causes juvenile epilepsy. Its epileptogenic potential in humans was unknown. Thus, we screened 18 patients with infantile epileptic spasms syndrome (IESS) and 98 patients with benign familial neonatal/infantile seizures (BFNS/BFIS) for the presence of PLPPR4 variants. A girl with IESS had inherited a PLPPR4-mutation (c.896C > G, NM_014839; p.T299S) from her father and an SCN1A-mutation from her mother (c.1622A > G, NM_006920; p.N541S). The PLPPR4-mutation was located in the third extracellular lysophosphatidic acid-interacting domain and in-utero electroporation (IUE) of the Prg-1p.T300S construct into neurons of Prg-1 knockout embryos demonstrated its inability to rescue the electrophysiological knockout phenotype. Electrophysiology on the recombinant SCN1Ap.N541S channel revealed partial loss-of-function. Another PLPPR4 variant (c.1034C > G, NM_014839; p.R345T) that was shown to result in a loss-of-function aggravated a BFNS/BFIS phenotype and also failed to suppress glutamatergic neurotransmission after IUE. The aggravating effect of Plppr4-haploinsufficiency on epileptogenesis was further verified using the kainate-model of epilepsy: double heterozygous Plppr4-/+|Scn1awt|p.R1648H mice exhibited higher seizure susceptibility than either wild-type, Plppr4-/+, or Scn1awt|p.R1648H littermates. Our study shows that a heterozygous PLPPR4 loss-of-function mutation may have a modifying effect on BFNS/BFIS and on SCN1A-related epilepsy in mice and humans. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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