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

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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., Vogt, J., Kintscher, M., Ponomarenko, A., Baumgart, J., Beed, P., Korotkova, T., Trimbuch, T., Panzer, A., Steinlein, O.K., Stephani, U., Escayg, A., Koko, M., Liu, Y., Lerche, H., Schmitz, D., 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
ISSN:	1047-3211
Publisher:	Oxford University Press
Volume:	33
Number:	12
Page Range:	7454-7467
Date:	15 June 2023
Official Publication:	https://doi.org/10.1093/cercor/bhad051
PubMed:	View item in PubMed

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