A 3′UTR polymorphism marks differential KLRG1 mRNA levels through disruption of a miR-584-5p binding site and associates with pemphigus foliaceus susceptibility

Gabriel A. Cipolla, Jong Kook Park, Liana A. de Oliveira, Sara Cristina Lobo-Alves, Rodrigo C. de Almeida, Ticiana D.J. Farias, Débora de S. Lemos, Danielle Malheiros, Robert M. Lavker, Maria Luiza Petzl-Erler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Genetic variations mapping to 3′ untranslated regions (3′UTRs) may overlap with microRNA (miRNA) binding sites, therefore potentially interfering with translation inhibition or messenger RNA (mRNA) degradation. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) located within the 3′UTRs of six candidate genes and predicted to interfere with miRNA ligation could account for disease-relevant differential mRNA levels. Focusing on pemphigus foliaceus (PF) – an autoimmune blistering skin condition with unique endemic patterns – we investigated whether nine 3′UTR SNPs from the CD1D, CTLA4, KLRD1, KLRG1, NKG7, and TNFSF13B genes differentially expressed in PF were disease-associated. The heterozygous genotype of the KLRG1 rs1805672 polymorphism was associated with increased predisposition to PF (A/G vs. A/A: P = 0.038; OR = 1.60), and a trend for augmented susceptibility was observed for carriers of the G allele (P = 0.094; OR = 1.44). In silico analyses suggested that rs1805672 G allele could disrupt binding of miR-584-5p, and indicated rs1805672 as an expression Quantitative Trait Locus (eQTL), with an effect on KLRG1 gene expression. Dual-luciferase assay showed that miR-584-5p mediated approximately 50% downregulation of the reporter gene's activity through the 3′UTR of KLRG1 harboring rs1805672 A allele (vs. miRNA-negative condition, P = 0.006). This silencing relationship was lost after site-directed mutation to G allele (vs. miRNA-negative condition, P = 0.391; vs. rs1805672 A allele, P = 0.005). Collectively, these results suggest that a disease-associated SNP located within the 3′UTR of KLRG1 directly interferes with miR-584-5p binding, allowing for KLRG1 mRNA differential accumulation, which in turn may contribute to pathogenesis of autoimmune diseases, such as pemphigus.

Original languageEnglish (US)
Pages (from-to)1306-1313
Number of pages8
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1859
Issue number10
DOIs
StatePublished - Oct 1 2016

Keywords

  • 3′UTR
  • Gene expression
  • KLRG1
  • eQTL
  • miR-584-5p
  • rs1805672

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics

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