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

Ellen Knierim; Johannes Vogt; Michael Kintscher; Alexey Ponomarenko; Jan Baumgart; Prateep Beed; Tatiana Korotkova; Thorsten Trimbuch; Axel Panzer; Ortrud K Steinlein; Ulrich Stephani; Andrew Escayg; Mahmoud Koko; Yuanyuan Liu; Holger Lerche; Dietmar Schmitz; Robert Nitsch; Markus Schuelke

doi:10.1093/cercor/bhad051

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

Cereb Cortex. 2023 Jun 8;33(12):7454-7467. doi: 10.1093/cercor/bhad051.

Authors

Ellen Knierim^{1

2}, Johannes Vogt³, Michael Kintscher^{4

5}, Alexey Ponomarenko^{4

6}, Jan Baumgart^{7

8}, Prateep Beed⁴, Tatiana Korotkova^{4

6}, Thorsten Trimbuch⁷, Axel Panzer⁹, Ortrud K Steinlein¹⁰, Ulrich Stephani¹¹, Andrew Escayg¹², Mahmoud Koko⁵, Yuanyuan Liu⁵, Holger Lerche⁵, Dietmar Schmitz^{1

4

13

14

15

16}, Robert Nitsch¹⁷, Markus Schuelke^{1

2}

Affiliations

¹ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, NeuroCure Clinical Research Center, 10117 Berlin, Germany.
² Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
³ 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.
⁴ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Neuroscience Research Center, 10117 Berlin, Germany.
⁵ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany.
⁶ Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
⁷ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Institute of Neurophysiology, 10117 Berlin, Germany.
⁸ Translational Animal Research Center (TARC), University Medical Center Mainz, 55128 Mainz, Germany.
⁹ Pediatric Neurology, DRK Kliniken-Westend, 14050 Berlin, Germany.
¹⁰ Institute of Human Genetics, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
¹¹ Department of Child and Adolescent Medicine II, University Medical Center of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
¹² Department of Human Genetics, Emory University, Atlanta, GA 30322, United States.
¹³ Humboldt-Universität zu Berlin, Bernstein Center for Computational Neuroscience, 10115 Berlin, Germany.
¹⁴ Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
¹⁵ German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany.
¹⁶ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Einstein Center for Neuroscience, 10117 Berlin, Germany.
¹⁷ Institute for Translational Neuroscience, Westfälische Wilhelms University, 48149 Münster, Germany.

PMID: 36977636
DOI: 10.1093/cercor/bhad051

Abstract

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.

Keywords: animal model; digenic inheritance; genetic disease; genetic epilepsy; ion channels; modifier gene; mutation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Epilepsy* / metabolism
Female
Hippocampus / metabolism
Humans
Mice
Mutation / genetics
NAV1.1 Voltage-Gated Sodium Channel / genetics
Phenotype
Seizures* / genetics
Seizures* / metabolism

Substances

NAV1.1 Voltage-Gated Sodium Channel
Prg-1 protein, mouse