Schizophrenia Patient Shows a Rare Interleukin 15 Receptor alpha Variant Disrupting Signal Transduction

Curr Mol Med. 2019;19(8):560-569. doi: 10.2174/1566524019666190617172054.

Abstract

Background: Schizophrenia is a complex and debilitating mental disorder with strong heritability. Its pathogenesis involves immune dysregulation. Interleukin 15 and interleukin 15 receptor alpha(IL-15Rα) are classical immune molecules. They also help maintain normal brain function, leading to our hypothesis that IL-15Rα gene(IL- 15RA) variants contribute to the pathogenesis of schizophrenia.

Objective: We determine whether the genetic variants of IL-15RA are associated with the development and progression of schizophrenia and whether IL-15RA single nucleotide polymorphism(SNP) plays a key role in downstream signaling transduction.

Methods and results: We sequenced IL-15RA exon from 132 Chinese schizophrenic patients and identified a rare variant(rs528238821) in a patient diagnosed with catatonic schizophrenia and ankylosing spondylitis(AS). We overexpressed this missense variant in cells driven by pBI-CMV vector. The cells showed attenuated STAT3 phosphorylation in response to interleukin15.

Conclusion: IL-15RA mutation is rare in schizophrenic patients but interfered with IL- 15Rα intracellular signal transduction. Given the similarity of symptoms of catatonic schizophrenia and the known phenotype of IL-15Rα knockout mice, gene variation might offer diagnostic value for sub-types of schizophrenia.

Keywords: IL-15RA; Interleukin 15 receptor alpha; STAT3 phosphorylation; interleukin 15; schizophrenia; single nucleotide polymorphism..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Asian People / genetics
  • Exons / genetics
  • HEK293 Cells
  • Humans
  • Interleukin-15 / physiology
  • Interleukin-15 Receptor alpha Subunit / deficiency
  • Interleukin-15 Receptor alpha Subunit / genetics*
  • Interleukin-15 Receptor alpha Subunit / physiology
  • Loss of Function Mutation
  • Male
  • Mice, Knockout
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Phosphorylation
  • Point Mutation*
  • Polymorphism, Single Nucleotide*
  • Protein Processing, Post-Translational
  • Recombinant Proteins / metabolism
  • STAT3 Transcription Factor / metabolism
  • Schizophrenia, Catatonic / genetics*
  • Schizophrenia, Paranoid / genetics*
  • Signal Transduction
  • Spondylitis, Ankylosing / genetics

Substances

  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human