Helmholtz Gemeinschaft


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

Item Type:Article
Title:Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype
Creators Name:Knierim, E. and Vogt, J. and Kintscher, M. and Ponomarenko, A. and Baumgart, J. and Beed, P. and Korotkova, T. and Trimbuch, T. and Panzer, A. and Steinlein, O.K. and Stephani, U. and Escayg, A. and Koko, M. and Liu, Y. and Lerche, H. and Schmitz, D. and Nitsch, R. and Schuelke, M.
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-1(p.T300S) construct into neurons of Prg-1 knockout embryos demonstrated its inability to rescue the electrophysiological knockout phenotype. Electrophysiology on the recombinant SCN1A(p.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(-/+)|Scn1a(wt|p.R1648H) mice exhibited higher seizure susceptibility than either wild-type, Plppr4(-/+), or Scn1a(wt|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:Genetic Epilepsy, Ion Channels, Mutation, Animal Model, Modifier Gene, Digenic Inheritance, Genetic Disease, Animals, Mice
Source:Cerebral Cortex
Publisher:Oxford University Press
Page Range:7454-7467
Date:15 June 2023
Official Publication:https://doi.org/10.1093/cercor/bhad051
PubMed:View item in PubMed

Repository Staff Only: item control page

Open Access
MDC Library