> Details

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

Reference
management

Bookmarks

Remove from
bookmarks

Share this on Whatsapp

Close

Bookmarks



You can manage bookmarks using lists, please log in to your user account for this.
  • Media type: E-Article
  • Title: Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype
  • Contributor: 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
  • Published: Oxford University Press (OUP), 2023
  • Published in: Cerebral Cortex, 33 (2023) 12, Seite 7454-7467
  • Language: English
  • DOI: 10.1093/cercor/bhad051
  • ISSN: 1047-3211; 1460-2199
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access