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

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.; Schuelke, M.

doi:10.1101/282871

bioRxiv · 10.1101/282871

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

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.·Schuelke, M.

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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-/+|Scn1awt/p.R1648Hmice exhibited higher seizure susceptibility than either wildtype, Prg1-/+, or Scn1awt/p.R1648H littermates. Our study provides evidence that PRG1-mutations have a potential modifying influence on SCN1A-related epilepsy in humans.

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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., Schuelke, M.. 2018-03-15. Mutant Plasticity Related Gene 1 (PRG1) acts as a potential modifier in SCN1A related epilepsy. https://doi.org/10.1101/282871

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