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

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

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  • Medientyp: E-Artikel
  • Titel: Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype
  • Beteiligte: Knierim, Ellen; Vogt, Johannes; Kintscher, Michael; Ponomarenko, Alexey; Baumgart, Jan; Beed, Prateep; Korotkova, Tatiana; Trimbuch, Thorsten; Panzer, Axel; Steinlein, Ortrud K; Stephani, Ulrich; Escayg, Andrew; Koko, Mahmoud; Liu, Yuanyuan; Lerche, Holger; Schmitz, Dietmar; Nitsch, Robert; Schuelke, Markus
  • Erschienen: Oxford University Press (OUP), 2023
  • Erschienen in: Cerebral Cortex, 33 (2023) 12, Seite 7454-7467
  • Sprache: Englisch
  • DOI: 10.1093/cercor/bhad051
  • ISSN: 1047-3211; 1460-2199
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: 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.
  • Zugangsstatus: Freier Zugang