HGNC Approved Gene Symbol: AHR
Cytogenetic location: 7p21.1 Genomic coordinates (GRCh38): 7:17,298,652-17,346,147 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p21.1 | ?Retinitis pigmentosa 85 | 618345 | Autosomal recessive | 3 |
The aryl hydrocarbon receptor (AHR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses (summary by Moura-Alves et al., 2014).
Ema et al. (1994) isolated human cDNA for the AHR gene, using mouse cDNA as a labeled probe. The deduced primary structure of human AHR showed an overall amino acid similarity of 72.5% with that of the mouse counterpart. Protein encoded by the AHR cDNA bound the inducer, TCDD, with a high affinity in a 9S complex form.
Using immunohistochemistry and Western blot analysis, Zhou et al. (2018) demonstrated expression of AHR in human retinal photoreceptors.
Halogenated aromatic hydrocarbons, represented by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are environmental pollutants that are produced by minor side-reactions in chemical manufacturing processes and by combustion of waste materials. These chemicals cause potent and pleiotropic toxicity, including teratogenesis, immune suppression, epithelial disorders, and tumor production in experimental animals. At the molecular level, aldehyde dehydrogenase, quinone reductase, and various drug-metabolizing enzymes are induced by the chemicals in some cultured cells and some tissues of experimental animals. All these biologic effects are thought to be mediated by an intracellular aryl hydrocarbon receptor (AHR) (summary by Ema et al., 1994).
A heterodimer of the dioxin receptor (AHR) and ARNT (126110), which are basic helix-loop-helix/PAS family transcription factors, mediates most of the toxic effects of dioxins. Ohtake et al. (2003) demonstrated that the agonist-activated AHR/ARNT heterodimer directly associates with the estrogen receptors ER-alpha (133430) and ER-beta (601663). They showed that this association results in the recruitment of unliganded estrogen receptor and the coactivator p300 (602700) to estrogen-responsive gene promoters, leading to activation of transcription and estrogenic effects. The function of liganded estrogen receptor was found to be attenuated. Estrogenic actions of AHR agonists were detected in wildtype ovariectomized mouse uteri, but were absent in Ahr -/- or Er-alpha -/- ovariectomized mice. Ohtake et al. (2003) concluded that their findings suggest a novel mechanism by which estrogen receptor-mediated signaling is modulated by a coregulatory-like function of activated AHR/ARNT, giving rise to adverse estrogen-related actions of dioxin-type environmental contaminants.
Ohtake et al. (2007) characterized a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which AHR is integrated as a component of a novel cullin-4B (300304) ubiquitin ligase complex, CUL4B(AHR). Complex assembly and ubiquitin ligase activity of CUL4B(AHR) in vitro and in vivo are dependent on the AHR ligand. In the CUL4B(AHR) complex, ligand-activated AHR acts as a substrate-specific adaptor component that targets sex steroid receptors for degradation. Ohtake et al. (2007) concluded that their findings uncovered a function for AHR as an atypical component of the ubiquitin ligase complex and demonstrated a nongenomic signaling pathway in which fat-soluble ligands regulate target protein-selective degradation through a ubiquitin ligase complex.
Quintana et al. (2008) found that activation of Ahr by a dioxin ligand induced functional regulatory T lymphocytes (Treg cells) expressing Foxp3 (300292) that were capable of suppressing experimental autoimmune encephalomyelitis (EAE) in mice. In contrast, activation of Ahr by a carbazole ligand boosted differentiation of T cells producing Il17 (see 603149) (Th17 cells), interfered with Treg development, and increased the severity of EAE in mice. Quintana et al. (2008) concluded that AHR regulates both Treg and Th17 cell differentiation in a ligand-specific fashion and may constitute a unique target for therapeutic immunomodulation.
Using FACS and RT-PCR analyses of mouse and human CD4 (186940)-positive T cells, Veldhoen et al. (2008) found that expression of AHR was restricted to Th17 cells and that AHR ligation resulted in production of IL22 (605330). Cd4-positive cells from mice lacking Ahr developed Th17 responses but failed to produce Il22 and did not show enhanced Th17 development. Activation of Ahr during induction of EAE accelerated disease onset and increased pathology in wildtype mice, but not in Ahr -/- mice. Veldhoen et al. (2008) concluded that environmental pollutants that activate AHR may initiate or augment autoimmune conditions.
Using an unbiased screen with primary human hematopoietic stem cells, Boitano et al. (2010) identified a purine derivative, StemRegenin-1 (SR1), that promotes the ex vivo expansion of CD34 (142230)-positive cells. Culture of hematopoietic stem cells with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies showed that SR1 acts by antagonizing the AHR. Boitano et al. (2010) concluded that the identification of SR1 and AHR modulation as a means to induce ex vivo hematopoietic stem cell expansion should facilitate the clinical use of hematopoietic stem cell therapy.
Opitz et al. (2011) identified the tryptophan catabolite kynurenine (kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumor cells via tryptophan 2,3-dioxygenase (TDO2; 191070), a liver- and neuron-derived trp-degrading enzyme. TDO-derived kyn suppresses antitumor immune responses and promotes tumor cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumors and is associated with malignant progression and poor survival. Opitz et al. (2011) concluded that because kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, their results provided evidence for a previously unidentified pathophysiologic function of the AHR with profound implications for cancer and immune biology.
Innate lymphoid cells (ILC) expressing the transcription factor ROR-gamma-t (see 602943) induce the postnatal formation of intestinal lymphoid follicles and regulate intestinal homeostasis. ROR-gamma-t-positive ILC express Ahr, a highly conserved, ligand-inducible transcription factor believed to control adaptation of multicellular organisms to environmental challenges. In mice, Kiss et al. (2011) showed that Ahr is required for the postnatal expansion of intestinal ROR-gamma-t-positive ILC and the formation of intestinal lymphoid follicles. Ahr activity within ROR-gamma-t-positive ILC could be induced by dietary ligands such as those contained in vegetables of the family Brassicaceae. Ahr-deficient mice were highly susceptible to infection with Citrobacter rodentium, a mouse model for attaching and effacing infections. Kiss et al. (2011) concluded that their results established a molecular link between nutrients and the formation of immune system components required to maintain intestinal homeostasis and resistance to infections.
Using Lxra (NR1H3; 602423) and Lxrb (NR1H2; 600380) double-knockout mice and Lxr agonists, Cui et al. (2011) observed Lxr-dependent amelioration of experimental autoimmune encephalomyelitis. Lxr overexpression decreased, whereas Lxr deficiency promoted, cytokine-driven mouse Th17 cell differentiation and polarization in vitro. In mouse, Srebp1 (SREBF1; 184756) was recruited to the E-box element on the Il17 promoter upon Lxr activation and interacted with Ahr to inhibit Il17 transcriptional activity. LXR activation in human cells also suppressed Th17 cell differentiation, promoted SREBP1 expression, and decreased AHR expression. Mutation and coimmunoprecipitation analyses showed that the putative active-site domain of mouse Ahr and the N-terminal acidic region of mouse Srebp1 were essential for Ahr-Srebp1 interaction. Cui et al. (2011) concluded that a downstream target of LXR, SREBP1, antagonizes AHR to suppress Th17 cell generation and autoimmunity.
Bessede et al. (2014) found that a first exposure of mice to lipopolysaccharide (LPS) activated the ligand-operated transcription factor Ahr and the hepatic enzyme Tdo2, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, Ahr engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase-1 (IDO1; 147435). Ahr complex-associated Src kinase activity promoted Ido1 phosphorylation and signaling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in gram-negative and gram-positive infections, pointing to a role for Ahr in contributing to host fitness.
The AHR is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. Moura-Alves et al. (2014) hypothesized that AHR evolved to sense not only environmental pollutants but also microbial insults. They characterized bacterial pigmented virulence factors, namely, the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AHR. Upon ligand binding, AHR activation leads to virulence factor degradation and to regulated cytokine and chemokine production. The relevance of AHR to host defense is underlined by heightened susceptibility of Ahr-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, Moura-Alves et al. (2014) demonstrated that AHR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a role for AHR as an intracellular pattern recognition receptor, and identified bacterial pigments as a class of pathogen-associated molecular patterns.
By inducing naive human CD4 T cells toward development of IL9 (146931)-producing T cells (Th9 cells) in the presence or absence of the active form of vitamin D (calcitriol), Takami et al. (2015) observed a calcitriol dose-dependent abrogation of IL9 protein and mRNA expression without inhibition of T-cell growth. The inhibition was IL10 (124092) independent in human cells, whereas in mice it was Il10 dependent. Calcitriol also reduced BATF (612476) protein and mRNA expression without altering expression of several other transcription factors involved in Th9 differentiation. Transcriptomic analysis revealed that AHR expression was important in Th9 differentiation, and expression of AHR was also reduced by calcitriol. An AHR antagonist inhibited Th9 development, and small interfering RNA to AHR reduced IL9 and BATF expression. Ligand-mediated activation of AHR partially restored BATF and IL9 expression. Takami et al. (2015) concluded that AHR and BATF are linked in Th9 differentiation and that calcitriol suppresses their expression and Th9 differentiation. The authors proposed that vitamin D deficiency may lead to enhanced Th9 differentiation, mast cell expansion, and allergic conditions.
Rentas et al. (2016) found that expression of the RNA-binding protein MSI2 (607897) was upregulated in primitive human cord blood hematopoietic stem cells (HSCs) and was downregulated with HSC differentiation. Overexpression of MSI2 in HSCs significantly promoted self-renewal phenotypes, whereas knockdown of MSI2 reduced HSC self-renewal. Global analysis of MSI2-mRNA interactions revealed that MSI2 repressed expression of AHR and AHR targets, particularly CYP1B1 (601771), which promotes HSC differentiation. Pharmacologic inhibition of CYP1B1 phenocopied the effect of MSI2 in promoting cord blood HSC self-renewal, and agonist-induced restoration of AHR activity reduced the effect of MSI2 overexpression on self-renewal. Cross-linking immunoprecipitation of MSI2 protein-RNA interactions, followed by sequencing and motif analysis, identified a consensus pentamer, (U/G)UAGU, within MSI2-binding sites. This motif was found in all regions of MSI2 target mRNAs, including coding regions, but predominantly mapped to 3-prime UTRs. Reporter gene assays and mutation analysis using the 3-prime UTRs of 2 putative MSI2 targets, CYP1B1 and HSP90 (HSP90AA1; 140571), which is also an AHR pathway component, confirmed that MSI2 directly downregulated translation of target mRNAs via the UAG motif. Rentas et al. (2016) concluded that MSI2 promotion of HSC self-renewal capacity is mainly due to inhibition of the AHR-CYP1B1 pathway.
Schiering et al. (2017) showed that dysregulated expression of Cyp1a1 (108330) in mice depletes the reservoir of natural Ahr ligands, generating a quasi Ahr-deficient state. Constitutive expression of Cyp1a1 throughout the body or restricted specifically to intestinal epithelial cells resulted in loss of Ahr-dependent type 3 innate lymphoid cells and T helper 17 cells, and increased susceptibility to enteric infection. The deleterious effects of excessive Ahr ligand degradation on intestinal immune functions could be counterbalanced by increasing the intake of Ahr ligands in the diet. Schiering et al. (2017) concluded that their data indicated that intestinal epithelial cells serve as gatekeepers for the supply of AHR ligands to the host and emphasized the importance of feedback control in modulating AHR pathway activation.
Obata et al. (2020) showed that the transcription factor AHR functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, Obata et al. (2020) demonstrated that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enabled these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator Cyp1a1, resulted in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restored intestinal motility. Obata et al. (2020) concluded that their experiments identified AHR signaling in enteric neurons as a regulatory node that integrates the luminal environment with the physiologic output of intestinal neural circuits to maintain gut homeostasis and health.
By fluorescence in situ hybridization and by DNA blot hybridization using human/mouse or human/Chinese hamster hybrid cell DNAs, Ema et al. (1994) assigned the AHR gene to 7p21.
By use of PCR analysis of somatic cell hybrids and fluorescence in situ hybridization of metaphase cells, Le Beau et al. (1994) localized the AHR gene to 7p21-p15. Micka et al. (1997) localized the AHR gene to 7p15 using fluorescence in situ hybridization. Performing linkage analysis in a 3-generation family, they showed with good probability that the high CYP1A1 (108330) inducibility phenotype segregates with the 7p15 region.
Retinitis Pigmentosa 85
In 2 affected members of a large consanguineous Indian family with retinitis pigmentosa (RP85; 618345), Zhou et al. (2018) identified homozygosity for a splice site mutation (c.1160+1G-A; 600253.0001) that segregated with disease and was not found in controls or public variant databases.
Associations Pending Confirmation
Micka et al. (1997) sequenced 93 nucleotides (corresponding to 31 amino acids) of exon 9 of the human AHR gene, which is the region corresponding to that containing the mouse ala375-to-val polymorphism, and found no nucleotide differences; val381 was present in all 5 individuals examined, 2 of whom showed 'high' and 3 of whom 'low' CYP1A1 inducibility.
To determine whether the aryl hydrocarbon receptor plays a role in modulating carcinogenesis through the induction of xenobiotic-metabolizing enzymes, Shimizu et al. (2000) studied Ahr-deficient mice exposed to benzo(a)pyrene, a widely distributed environmental carcinogen. They found that the carcinogenicity of this agent was lost in Ahr-deficient mice. Shimizu et al. (2000) concluded that the carcinogenic action of benzo(a)pyrene can be determined primarily by AHR, a transcriptional regulator of the gene for CYP1A1.
Polycyclic aromatic hydrocarbons (PAHs) are toxic chemicals released into the environment by fossil fuel combustion. Oocyte destruction and ovarian failure occur in PAH-treated mice, and cigarette smoking causes early menopause in women. In many cells, PAHs activate the AHR, a member of the Per-Arnt-Sim family of transcription factors. The AHR is also activated by dioxin, one of the most intensively studied environmental contaminants. Matikainen et al. (2001) demonstrated that an exposure of mice to PAHs induces the expression of Bax (600040) in oocytes, followed by apoptosis. Ovarian damage caused by PAHs is prevented by Ahr or Bax inactivation. Oocytes microinjected with a Bax promoter-reporter construct show Ahr-dependent transcriptional activation after PAH, but not dioxin, treatment, consistent with findings that dioxin is not cytotoxic to oocytes. This difference in the action of PAHs versus dioxin is conveyed by a single basepair flanking each Ahr response element in the Bax promoter. Oocytes in human ovarian biopsies grafted into immunodeficient mice also accumulated Bax and underwent apoptosis after PAH exposure in vivo. Thus, Matikainen et al. (2001) concluded that AHR-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure.
Environmental pollutants, notably polychlorinated dioxins and biphenyls, represent well-characterized AHR ligands. The dioxin/AHR functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding xenobiotic metabolizing enzymes. Loss-of-function (gene-disruption) studies in mice had demonstrated that AHR is involved in toxic effects of dioxins but had not yielded unequivocal results concerning the physiologic function of the receptor. To unravel the biologic functions of AHR, Andersson et al. (2002) performed gain-of-function studies. A constitutively active AHR expressed in transgenic mice reduced the life span of the mice and induced tumors in the glandular part of the stomach, demonstrating the oncogenic potential of the AHR and implicating the receptor in regulation of cell proliferation.
By targeted disruption of the Ahr gene in mice, Walisser et al. (2005) demonstrated that Ahr signaling in endothelial/hematopoietic cells is necessary for developmental closure of the ductus venosus, whereas Ahr signaling in hepatocytes is necessary to generate adaptive and toxic responses to dioxin exposure. They concluded that cell-specific receptor signaling generates distinct AHR-dependent physiologic outcomes.
Zhou et al. (2018) found that mice with retina-specific Arh knockout had decreased retinal scotopic responses on electroretinography at age 12 months compared to controls. Mean b-wave amplitude was reduced by approximately 30% and a-wave amplitude by 15% in the mutant mice. Analysis of retinal sections showed a retinal degeneration phenotype, with a reduced number of photoreceptor cells per row in 18-month-old mutant mice compared to controls, as well as an outer segment that was thinner than that of wildtype mice. Immunostaining showed increased expression of the proapoptotic CCAAT/enhancer-binding protein homologous protein (CHOP; 126337) in the Ahr knockout retinas, indicating cellular stress. TUNEL analysis demonstrated increased cell death in the mutant retina.
In 2 distantly related Indian boys (RD-CIP-78 and RD-ICP-79) with retinitis pigmentosa (RP85; 618345), Zhou et al. (2018) identified homozygosity for a splice site mutation (c.1160+1G-A, NM_001621.4) in intron 9 of the AHR gene that segregated fully with disease in the family and was not found in 1,000 ethnically matched controls or in the gnomAD database. Analysis of patient cDNA showed that the mutation caused a frameshift due to skipping of the 142-bp exon 9, resulting in a premature termination codon (Arg339fsTer7) with loss of the glutamine-rich transcriptional activation binding domain.
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