SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy

J Cell Mol Med. 2018 Mar;22(3):1883-1893. doi: 10.1111/jcmm.13473. Epub 2018 Jan 24.

Abstract

D-serine is a predominant N-methyl-D-aspartate receptor co-agonist with glutamate, and excessive activation of the receptor plays a substantial role in epileptic seizures. Serine racemase (SRR) is responsible for transforming L-serine to D-serine. In this study, we aimed to investigate the genetic roles of SRR and a neighbouring gene, nonsense-mediated mRNA decay factor (SMG6), in temporal lobe epilepsy (TLE). Here, a total of 496 TLE patients and 528 healthy individuals were successfully genotyped for three SRR tag single nucleotide polymorphisms. The frequencies of the GG genotype at rs4523957 T > G were reduced in the TLE cases in the initial cohort (cohort 1) and were confirmed in the independent cohort (cohort 2). An analysis of all TLE cases in cohort 1 + 2 revealed that the seizure frequency and drug-resistant incidence were significantly decreased in carriers of the GG genotype at rs4523957. Intriguingly, the activity of the SMG6 promoter with the mutant allele at rs4523957 decreased by 22% in the dual-luciferase assay, and up-regulated expression of SMG6 was observed in an epilepsy rat model. This study provides the first demonstration that the GG genotype is a protective marker against TLE. In particular, variation at rs4523957 likely inhibits SMG6 transcription and plays a key role against susceptibility to and severity of TLE. The significance of SMG6 hyperfunction in epileptic seizures deserves to be investigated in future studies.

Keywords: N-methyl-D-aspartate receptor; SMG6; serine racemase; temporal lobe epilepsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Case-Control Studies
  • Cohort Studies
  • Computational Biology
  • Disease Models, Animal
  • Epilepsy, Temporal Lobe / genetics*
  • Epilepsy, Temporal Lobe / metabolism
  • Epilepsy, Temporal Lobe / pathology
  • Female
  • Gene Expression Regulation
  • Genes, Reporter
  • Genotype
  • Glutamic Acid / metabolism
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Introns
  • Luciferases / genetics
  • Luciferases / metabolism
  • Male
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Racemases and Epimerases / genetics*
  • Racemases and Epimerases / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Serine / metabolism
  • Signal Transduction
  • Telomerase / genetics*
  • Telomerase / metabolism

Substances

  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Serine
  • Luciferases
  • Telomerase
  • SMG6 protein, human
  • Racemases and Epimerases
  • serine racemase