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.
Footnotes
↵§ these authors jointly directed the work
ellen.knierim{at}charite.de; johannes.vogt{at}unimedizin-mainz.de; michael.kintscher{at}epfl.ch; ponomarenko{at}fmp-berlin.de; jan.baumgart{at}unimedizin-mainz.de; prateep.beed{at}charite.de; korotkova{at}fmp-berlin.de; thorsten.trimbuch{at}charite.de; a.panzer{at}drk-kliniken-berlin.de; stephani{at}pedneuro.ni-kiel.de; aescayg{at}emory.edu; holger.lerche{at}uni-tuebingen.de; nitschr{at}uni-muenster.de; dietmar.schmitz{at}charite.de; markus.schuelke{at}charite.de