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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: |
Knierim, E.  ORCID: https://orcid.org/0000-0002-4769-7322, Vogt, J. ORCID: https://orcid.org/0000-0003-2439-8247, Kintscher, M. ORCID: https://orcid.org/0000-0003-2355-1369, Ponomarenko, A. ORCID: https://orcid.org/0000-0002-5185-0107, Baumgart, J. ORCID: https://orcid.org/0000-0003-1996-4267, Beed, P. ORCID: https://orcid.org/0000-0003-1044-8223, Korotkova, T. ORCID: https://orcid.org/0000-0001-7964-9838, Trimbuch, T. ORCID: https://orcid.org/0000-0001-7512-8955, Panzer, A. ORCID: https://orcid.org/0000-0002-7734-5299, Steinlein, O.K. ORCID: https://orcid.org/0000-0003-4311-6276, Stephani, U. ORCID: https://orcid.org/0000-0003-0493-7522, Escayg, A. ORCID: https://orcid.org/0000-0001-7158-2878, Koko, M. ORCID: https://orcid.org/0000-0001-9512-0184, Liu, Y. ORCID: https://orcid.org/0000-0002-4273-821X, Lerche, H. ORCID: https://orcid.org/0000-0002-1783-8710, Schmitz, D. ORCID: https://orcid.org/0000-0003-2741-5241, Nitsch, R. ORCID: https://orcid.org/0000-0002-6885-2555 and Schuelke, M. ORCID: https://orcid.org/0000-0003-2824-3891
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| 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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