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

Item Type:Preprint
Title:Mutant Plasticity Related Gene 1 (PRG1) acts as a potential modifier in SCN1A related epilepsy
Creators Name:Knierim, E. and Vogt, J. and Kintscher, M. and Ponomarenko, A. and Baumgart, J. and Sanker Beed, P. and Korotkova, T. and Trimbuch, T. and Panzer, A. and Stephani, U. and Escayg, A. and Lerche, H. and Nitsch, R. and 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
Publisher:Cold Spring Harbor Laboratory Press
Article Number:282871
Date:15 March 2018
Official Publication:https://doi.org/10.1101/282871

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