Genetic determinants of neuroglobin transcription

R. Wang, E. Halper-Stromberg, M. Szymanski-Pierce, Susan Bassett, Dimitrios Avramopoulos

Research output: Contribution to journalArticle

Abstract

Neuroglobin (NGB) is a neuron-specific vertebrate globin shown to protect against hypoxia, ischemia, oxidative stress and the toxic effects of Amyloid-beta. Following on our and others' results highlighting the importance of NGB expression in disease, we searched for genetic determinants of its expression. We found that a microRNA expressed with the NGB transcript shows significant target enrichments in the angiogenesis pathway and the Alzheimer disease/presenilin pathway. Using reporter constructs we identified potential promoter/enhancer elements between the transcription start site and 1,142 bp upstream. Using 184 post-mortem temporal lobe samples we replicated the reported negative effect of age, and after genotyping tagging SNPs we found one (rs981471) showing a significant correlation with the gene's expression and another (rs8014408) showing an interaction with age, the rare C allele being correlated with higher expression and faster decline. The two SNPs are towards the 3 end of NGB within the same LD block, 52 Kb apart and modestly correlated (r 2∈=∈0.5). Next generation sequencing of the same 184 temporal lobe samples and 79 confirmed AD patients across the entire gene region (including >12 Kb on the 3 and 5 flank) revealed limited coding variation, suggesting purifying selection of NGB, but did not identify regulatory or disease associated rare variants. A dinucleotide repeat in intron 1 with extensive evidence of functionality showed interesting but inconclusive results, as it was not amenable to further molecular analysis.

Original languageEnglish (US)
Pages (from-to)65-75
Number of pages11
JournalNeurogenetics
Volume15
Issue number1
DOIs
Publication statusPublished - 2014

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Keywords

  • Alzheimer's disease
  • Gene expression
  • Genetics
  • Neuroglobin
  • Polymorphism
  • Promoter
  • Stroke
  • Transcription

ASJC Scopus subject areas

  • Genetics(clinical)
  • Cellular and Molecular Neuroscience
  • Genetics

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