Mutant Plasticity Related Gene 1 (PRG1) acts as a potential modifier in SCN1A related epilepsy

Tools

Item Type:	Preprint
Title:	Mutant Plasticity Related Gene 1 (PRG1) acts as a potential modifier in SCN1A related epilepsy
Creators Name:	Knierim, E., Vogt, J., Kintscher, M., Ponomarenko, A., Baumgart, J., Sanker Beed, P., Korotkova, T., Trimbuch, T., Panzer, A., Stephani, U., Escayg, A., Lerche, H., Nitsch, R., Schmitz, D. and Schuelke, M.
Abstract:	Plasticity related gene 1 encodes a cerebral neuron-specific synaptic transmembrane protein that modulates hippocampal excitatory transmission on glutamatergic neurons. In mice, homozygous Prg1-deficiency results in juvenile epilepsy. Screening a cohort of 18 patients with infantile spasms (West syndrome), we identified one patient with a heterozygous mutation in the highly conserved third extracellular phosphatase domain (p.T299S). The functional relevance of this mutation was verified by in-utero electroporation of a mutant Prg1 construct into neurons of Prg1-knockout embryos, and the subsequent inability of hippocampal neurons to rescue the knockout phenotype on the single cell level. Whole exome sequencing revealed the index patient to additionally harbor a novel heterozygous SCN1A variant (p.N541S) that was inherited from her healthy mother. Only the affected child carried both heterozygous PRG1 and SCN1A mutations. The aggravating effect of Prg1-haploinsufficiency on the epileptic phenotype was verified using the kainate-model of epilepsy. Double heterozygous Prg1(-/+)\|Scn1a(wt/p.R1648H) mice exhibited higher seizure susceptibility than either wildtype, Prg1(-/+), or Scn1a(wt/p.R1648H) littermates. Our study provides evidence that PRG1-mutations have a potential modifying influence on SCN1A-related epilepsy in humans.
Keywords:	PRG1, PLPPR4, SCN1A, Genetic Modifier, West Syndrome
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	282871
Date:	15 March 2018
Official Publication:	https://doi.org/10.1101/282871

Repository Staff Only: item control page