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Genetic determinants of neuroglobin transcription

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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.

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Acknowledgements

We thank Dr. Francine Benes of the Harvard Brain Tissue resource center for providing brain tissue. We thank Dr Andrew McCallion and Dr David Valle for conversations, and expert advice in many aspects of the project. This work was supported by NIA grants to DA and SSB (RO1AG022099 and RO1AG021804) and an award from the Neurosciences Education and Research Foundation to DA.

Conflict of interest

The authors have no conflicts of interest to report.

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Authors and Affiliations

  1. Department of Psychiatry, Johns Hopkins University, School of Medicine, 733 North Broadway, MRB-507, Baltimore, MD, 21205, USA

    R. Wang, S. S. Bassett & D. Avramopoulos

  2. McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, School of Medicine, 733 North Broadway, MRB-507, Baltimore, MD, 21205, USA

    E. Halper-Stromberg, M. Szymanski-Pierce & D. Avramopoulos

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  1. R. Wang
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Correspondence to D. Avramopoulos.

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Wang, R., Halper-Stromberg, E., Szymanski-Pierce, M. et al. Genetic determinants of neuroglobin transcription. Neurogenetics 15, 65–75 (2014). https://doi.org/10.1007/s10048-013-0388-3

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