Abstract
High-density mapping of mammalian genomes has enabled a wide range of genetic investigations including the mapping of polygenic traits, determination of quantitative trait loci, and phylogenetic comparison. Genome sequencing analysis of inbred mouse strains has identified high-density single nucleotide polymorphisms (SNPs) for investigation of complex traits, which has become a useful tool for biomedical research of human disease to alleviate ethical and practical problems of experimentation in humans. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) encodes a key host defense transcription factor. This review describes genetic characteristics of human NRF2 and its homologs in other vertebrate species. NRF2 is evolutionally conserved and shares sequence homology among species. Compilation of publically available SNPs and other genetic mutations shows that human NRF2 is highly polymorphic with a mutagenic frequency of 1 per every 72 bp. Functional at-risk alleles and haplotypes have been demonstrated in various human disorders. In addition, other pathogenic alterations including somatic mutations and misregulated epigenetic processes in NRF2 have led to oncogenic cell survival. Comprehensive information from the current review addresses association of NRF2 variation and disease phenotypes and supports the new insights into therapeutic strategies.
Highlights
The gene nuclear factor-like 2 (NFE2L2) or more commonly the used synonym nuclear factor erythroid 2- (NF-E2-) related factor 2 (NRF2) and its mouse homolog (Nfe2l2, Nrf2) encode a ubiquitous transcription factor belonging to the basic leucine zipper protein family [1, 2]
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is evolutionally conserved with high-sequence homology in many species
Certain singlenucleotide polymorphisms (SNPs) or haplotypes have been identified in various diseases as “at-risk” alleles and are related to functional alterations
Summary
The gene nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) or more commonly the used synonym nuclear factor erythroid 2- (NF-E2-) related factor 2 (NRF2) and its mouse homolog (Nfe2l2, Nrf2) encode a ubiquitous transcription factor belonging to the basic leucine zipper (bZIP) protein family [1, 2]. The NRF2-ARE pathway has emerged in mechanisms of human diseases in which oxidative stress is implicated. Three lines of gene-targeted (knockout) mice were generated by Drs M. Kelch-like ECH-activating protein 1 (KEAP1 for humans, Keap for mice, or iNrf for rats) is a cytoplasmic suppressor of NRF2 and is critical in NRF2 homeostasis and activity [10]. I address genetic aspects of human NRF2 and its homologs in other vertebrate species. The current review does not deal with mutations in other species, recent characterization of nrf mutant zebrafish which were hypersensitive to environmental toxicants [13] provides a useful investigational tool
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