Alternative titles; symbols
HGNC Approved Gene Symbol: HMOX1
SNOMEDCT: 1230003009;
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:35,381,096-35,394,207 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | {Pulmonary disease, chronic obstructive, susceptibility to} | 606963 | 3 | |
| Heme oxygenase-1 deficiency | 614034 | Autosomal recessive | 3 |
The HMOX1 gene encodes heme oxygenase, the rate limiting step in the catabolism of heme to form biliverdin, which is subsequently converted to bilirubin by biliverdin reductase (109750), free iron, and carbon monoxide. Heme oxygenase activity is induced by its substrate heme and by various nonheme substances (Guenegou et al., 2006).
Yoshida et al. (1988) increased heme oxygenase activity and mRNA level in human macrophages by treatment with hemin. Using poly(A)-rich RNA from these macrophages, they constructed a cDNA library and isolated a human heme oxygenase cDNA by screening with a rat cDNA. The nucleotide sequence showed that the deduced heme oxygenase is composed of 288 amino acids with a molecular mass of 32,800 Da. The homology in amino acid sequence between rat and human heme oxygenase was 80%.
Heme oxygenase occurs as 2 isozymes, an inducible heme oxygenase-1 (HMOX1) and a constitutive heme oxygenase-2 (HMOX2; 141251). Using polymerase chain reaction to study a mapping panel of human/rodent somatic cell hybrids, Kutty et al. (1994) localized HMOX1 to chromosome 22. By fluorescence in situ hybridization (FISH), they refined the assignment to 22q12. Seroussi et al. (1999) characterized a 190.3-kb contig in human 22q13.1 and identified the TOM1 (604700) and HMG2L1 (604702) genes, as well as the previously identified HMOX1 and MCM5 (602696) genes. The order of these genes is cen--HMG2L1--TOM1--HMOX1--MCM5--tel. All are oriented in a 5-prime to 3-prime direction from centromere to telomere.
Saito-Ohara et al. (1997) used FISH to assign the mouse Hmox1 gene to chromosome 10C1. However, Seroussi et al. (1999) mapped the mouse Hmox1 gene to 8C1 using FISH.
Using immunoprecipitation studies, Takahashi et al. (2000) showed that amyloid precursor protein (APP; 104760) and amyloid precursor-like protein (APLP1; 104775) bound to HMOX1 and HMOX2 in the endoplasmic reticulum and inhibited heme oxygenase activity by 25 to 35% in vitro. Familial Alzheimer disease (AD; 104300)-associated APP mutations showed greater inhibition (45 to 50%) of heme oxygenase. As heme oxygenase shows antioxidative effects, the authors hypothesized that APP-mediated inhibition of heme oxygenase may result in increased oxidative neurotoxicity in AD.
He et al. (2001) found that a dimer of mammalian Nrf2 (NFE2L2; 600492) and Atf4 (604064) bound a stress response element (StRE) sequence from Ho1, an Nrf2 target gene. CdCl2, an Ho1 inducer, increased expression of Atf4 in mouse hepatoma cells prior to induction of Ho1. A dominant-negative Atf4 mutant inhibited basal and CdCl2-induced expression of an StRE-dependent construct in hepatoma cells, but it only inhibited basal expression in a human mammary epithelial cell line. He et al. (2001) concluded that ATF4 regulates HO1 expression in a cell-specific manner, possibly in a complex with NRF2.
Lee and Chau (2002) showed that IL10, but not IL6 (147620), induces expression of Hmox1 in mouse macrophages through the p38 MAP kinase (MAPK14; 600289), but not the ERK (see 176948) or JNK (see 601158), pathway. Western blot analysis showed that treatment with Hmox1 antisense or hemoglobin (HBG1; 142200), a carbon monoxide scavenger, attenuated the IL10-mediated suppression of lipopolysaccharide-induced TNF (191160), INOS (see 163730), and MMP9 (120361) production, suggesting that carbon monoxide mediates the inhibitory effect of IL10 on inflammatory mediator production. Administration of IL10 to mice also induced Hmox1 and protected mice from lipopolysaccharide-induced septic shock. The protection was reversed in mice also receiving an Hmox1 inhibitor, zinc protoporphyrin IX. In these mice, protection was restored by carbon monoxide treatment.
Systemic mastocytosis is myeloid neoplasm characterized by increased survival and accumulation of neoplastic mast cells. Kondo et al. (2007) showed that both ligand-activated wildtype KIT (164920) and KIT carrying the systemic mastocytosis-associated asp816-to-val mutation (D816V; 164920.0009) induced HSP32 promoter activity and expression of HSP32 mRNA and protein. Moreover, pharmacologic inhibitors of HSP32 inhibited proliferation and induced apoptosis in neoplastic mast cells. Kondo et al. (2007) concluded that HSP32 supports neoplastic mast cell survival.
Heme Oxygenase 1 Deficiency
In a patient with heme oxygenase-1 deficiency (HMOX1D; 614034), Yachie et al. (1999) identified compound heterozygosity for 2 mutations in the HMOX1 gene: complete loss of exon 2 of the maternal allele (141250.0001) and a 2-nucleotide deletion in exon 3 of the paternal allele (141250.0002); a normal HMOX1 gene contains 5 exons.
In a 15-year-old girl with HMOX1D, Radhakrishnan et al. (2011) identified a homozygous nonsense mutation in the HMOX1 gene (R44X; 141250.0004).
In a 2-year-old boy with HMOX1D, Radhakrishnan et al. (2011) identified homozygosity for the R44X mutation in the HMOX1 gene.
In a boy, born of consanguineous Turkish parents, with HMOX1D, Greil et al. (2016) identified a homozygous missense mutation in the HMOX1 gene (G139V; 141250.0005) that segregated with the disorder in the family. The mutation is located in the catalytic domain of the enzyme. The authors noted that replacement of gly139 has been shown to cause loss of oxygenase activity but increased peroxidase activity. The patient had hemophagocytic lymphohistiocytosis.
In an Iranian boy with HMOX1D, who was born of consanguineous parents, Tahghighi et al. (2019) identified a homozygous nonsense mutation in the HMOX1 gene (K204X; 141250.0006). The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents.
In a boy with HMOX1D, Chau et al. (2020) identified compound heterozygous mutations in the HMOX1 gene (141250.0007-141250.0008). The mutations were identified by whole-exome sequencing. Each parent was heterozygous for one of the mutations.
Possible Role in Lung Disease
Among 201 smokers, Yamada et al. (2000) found an association between chronic pulmonary emphysema (CPE), which is a sign of chronic obstructive pulmonary disease (COPD; 606963) and a longer repeat length polymorphism in the promoter region of the HMOX1 gene (141250.0003). The polymorphisms were grouped into 3 classes: class S alleles (less than 25 repeats), class M alleles (25 to 29 repeats), and class L alleles (30 or more repeats). The proportion of allele frequencies in class L, as well as the proportion of genotypic frequencies in the group with class L alleles (L/L, L/M, and L/S), was significantly higher in smokers with CPE than in smokers without CPE. These findings suggested that the large size of a (GT)n repeat in the HMOX1 gene promoter may reduce HMOX1 inducibility by reactive oxygen species in cigarette smoke, thereby resulting in the development of CPE.
Kikuchi et al. (2005) screened the HMOX1 gene for (GT)n repeat length in 151 Japanese patients with lung adenocarcinoma (211980) and 153 controls. The proportion of L allele carriers was significantly higher among patients than controls (p = 0.02); the adjusted odds ratio for lung adenocarcinoma for L allele carriers was 1.8 (95% CI, 1.1-3.0) compared with non-L allele carriers. The risk of lung adenocarcinoma for L allele carriers versus non-L allele carriers was greatly increased in the group of male smokers (OR = 3.3; 95% CI, 1.5-7.4; p = 0.004); however, in female nonsmokers, the proportion of L allele carriers did not differ between patients and controls, nor did it differ between 108 patients with lung squamous cell carcinoma and 100 controls. Kikuchi et al. (2005) suggested that a large (GT)n repeat in the HMOX1 gene promoter may be associated with the development of lung adenocarcinoma in Japanese male smokers.
Yasuda et al. (2006) analyzed the length of (GT)n repeats in the HMOX1 promoter in 200 elderly Japanese patients with pneumonia and 200 controls. The frequencies of the L allele (33 or more repeats) and of L-allele genotypes (L/L, L/M, L/S) were significantly higher in patients with pneumonia than in controls (p = 0.0001 and p = 0.001, respectively). The adjusted odds ratio for L-allele carriers vs. non-L-allele carriers was 2.1. Yasuda et al. (2006) suggested that a large (GT)n repeat in the HMOX1 gene promoter may be associated with susceptibility to pneumonia in the older Japanese population.
Possible Role in Other Diseases
Chen et al. (2002) tested the association of microsatellite polymorphism in the promoter region of the human HMOX1 gene with the risk of coronary artery disease in patients with type 2 diabetes mellitus (T2D; 125853). They examined the allele frequencies of (GT)n repeats in this gene in 474 patients with coronary artery disease and in 322 controls. Among patients with T2D, the frequencies of the L alleles (more than 32 repeats) and proportion of genotypes with L alleles were significantly higher in those with coronary artery disease than in those without. Chen et al. (2002) suggested that patients with T2D carrying longer (GT)n repeats might have higher oxidative stress and increased susceptibility to the development of coronary artery disease.
Carbon monoxide can arrest cellular respiration, but paradoxically, it is synthesized endogenously by heme oxygenase type 1 in response to ischemic stress. Hmox1 -/- mice exhibited lethal ischemic lung injury, but were rescued from death by inhaled carbon monoxide. Carbon monoxide drove ischemic protection by activating soluble guanylate cyclase and thereby suppressed hypoxic induction of the gene encoding plasminogen activator inhibitor-1 (PAI1; 173360) in mononuclear phagocytes, which reduced accrual of microvascular fibrin. Carbon monoxide-mediated ischemic protection observed in wildtype mice was lost in mice null for the gene encoding PAI1. Fujita et al. (2001) concluded that their data established a fundamental link between carbon monoxide and prevention of ischemic injury based on the ability of carbon monoxide to derepress the fibrinolytic axis.
Wagener et al. (2003) investigated the involvement of heme and its degrading enzyme heme oxygenase in the inflammatory process during wound healing, studying Wistar rats. They observed that heme directly accumulates at the edges of a wound and that this coincided with an increased adhesion molecule expression and the recruitment of leukocytes. Intradermal administration of heme 24 hours before injury resulted in heme-induced influx of both macrophages and granulocytes. Heme oxygenase-1 was significantly expressed in the epithelium of both the mucosa and the skin of animals without wounds. On inflammation, its expression increased, particularly in infiltrating cells during the resolution phase of inflammation. They interpreted their results as indicating that local release of heme may be a physiologic trigger to start inflammatory processes, whereas heme oxygenase 1 antagonizes inflammation by attenuating adhesive interactions and cellular infiltration. The basal level of heme oxygenase expression in the skin may serve as a first protective environment against acute oxidative and inflammatory insults.
Using Western blotting in organ homogenates, Belcher et al. (2006) demonstrated that HMOX1 is upregulated in transgenic sickle (see 603903) mice compared to controls. Treatment of sickle mice with hemin further increased HMOX1 expression and inhibited hypoxia/reoxygenation-induced stasis, leukocyte-endothelium interactions, and NFKB (see 164011), VCAM1 (192225), and ICAM1 (147840) expression. Heme oxygenase inhibition by tin protoporphyrin exacerbated vascular stasis in sickle mice, whereas treatment with the HMOX1 products, carbon monoxide or biliverdin, inhibited stasis and NFKB, VCAM1, and ICAM1 expression. Local subcutaneous administration of an HMOX1-adenovirus construct increased HMOX1 and inhibited hypoxia/reoxygenation-induced stasis in the skin of sickle mice. Belcher et al. (2006) concluded that HMOX1 plays a vital role in the inhibition of vasoocclusion in transgenic sickle mice.
Pamplona et al. (2007) noted that experimental cerebral malaria (ECM), a model of human cerebral malaria (see 611162), develops in C57BL/6 mice, but not BALB/c mice, after infection with the rodent Plasmodium species, P. berghei ANKA. Using quantitative RT-PCR, they showed that Hmox1 was upregulated to a greater extent in BALB/c mice than in C57BL/6 mice after P. berghei infection. Unlike wildtype BALB/c mice, 83% of BALB/c mice lacking Hmox1 developed ECM, and 78% of wildtype BALB/c developed ECM following inhibition of Hmox1 activity. Pharmacologic induction of Hmox1 or exposure to the Hmox1 end product, CO, in C57BL/6 mice reduced ECM frequency to 10% or less. Neither Hmox1 or CO affected parasitemia, but both prevented blood-brain barrier disruption, brain microvasculature congestion, and neuroinflammation, including inhibition of Cd8 (see 186910)-positive T-cell brain sequestration. Pamplona et al. (2007) showed that CO bound to hemoglobin, thereby preventing hemoglobin oxidation and generation of free heme, a molecule required for triggering of ECM.
Seixas et al. (2009) showed that Hmox1 -/- BALB/c mice developed a form of hepatic failure with 100% lethality following infection with the rodent malaria parasite, P. chabaudi, similar to the 75% lethality observed in P. chabaudi-infected DBA/2 mice. In contrast, P. chabaudi-infected wildtype mice showed no lethality due to their ability to prevent the Tnf-mediated apoptotic cytotoxic effects of free heme. Treatment with the antioxidant N-acetylcysteine prevented hepatic failure in DBA/2 mice following infection, without reducing parasite burden. Seixas et al. (2009) concluded that HMOX1 limits malaria disease by protecting tissues from the harmful effects of free heme.
In the first reported patient with heme oxygenase-1 deficiency (HMOX1D; 614034), Yachie et al. (1999) described compound heterozygosity for 2 HMOX1 mutations: a deletion of exon 2 inherited from the mother and a 2-nucleotide deletion in exon 3 inherited from the father (141250.0002).
For discussion of the 2-bp deletion in the HMOX1 gene that was found in compound heterozygosity in a patient with heme oxygenase-1 deficiency (HMOX1D; 614034) by Yachie et al. (1999), see 141250.0001.
A (GT)n dinucleotide repeat in the 5-prime promoter region of the human HMOX1 gene shows a length polymorphism. In cultured cell lines, Yamada et al. (2000) demonstrated that a low number of (GT)n repeats was related to both increased HMOX1 basal promoter activity and transcriptional upregulation in response to oxidants. Cigarette smoke, containing reactive oxygen species, is the most important risk factor for chronic pulmonary emphysema (CPE), which is a sign of chronic obstructive pulmonary disease (COPD; 606963). HMOX1 plays a protective role as an antioxidant in the lung. Among 201 smokers, Yamada et al. (2000) found an association between CPE and the longer promoter polymorphism. The polymorphisms were grouped into 3 classes: class S alleles (less than 25 repeats), class M alleles (25 to 29 repeats), and class L alleles (30 or more repeats). The proportion of allele frequencies in class L, as well as the proportion of genotypic frequencies in the group with class L alleles (L/L, L/M, and L/S), was significantly higher in smokers with CPE than in smokers without CPE. These findings suggested that the large size of a (GT)n repeat in the HMOX1 gene promoter may reduce HMOX1 inducibility by reactive oxygen species in cigarette smoke, thereby resulting in the development of CPE.
Among 749 French adults, including 40% who never smoked, Guenegou et al. (2006) observed an association between carriers of the long (L) allele of the (GT)n polymorphism and decreased lung function, as assessed by forced expiratory volume in 1 second (FEV1) and FEV1/forced ventilatory capacity (FVC) ratio, over an 8-year period (1992 to 2000). At the 8-year follow-up, the mean annual FEV1 and FEV1/FVC declines in patients with 1 or 2 L alleles were -30.9 ml/year and -1.8 U/year. FEV1/FVC decline was steeper in L allele carriers than in noncarriers (-2.6 versus -1.5, p = 0.07). There was a strong interaction between the L allele and smoking. At the 8-year follow-up, the L allele was associated with lower FEV1 and FEV1/FVC in heavy smokers only. Baseline heavy smokers carrying the L allele showed the steepest FEV1 decline (-62.0 ml/year) and the steepest FEV1/FVC decline (-8.8 U/year) (p for interaction = 0.009 and 0.0006, respectively). Guenegou et al. (2006) suggested that a long HMOX1 gene promoter in heavy smokers is associated with susceptibility to developing airway obstruction.
Siedlinski et al. (2008) followed 1,390 Dutch individuals, including 67.9% who never smoked, with FEV1 measurements every 3 years for 25 years (1965 to 1990). They found that the M/L and L/L genotype constituted a risk factor for accelerated FEV1 decline in the total population compared with any other genotype. The mean adjusted change in FEV1 for the M/L and L/L genotype pool was -24.2 ml/year. S/L, S/S, S/M and M/M genotypes provided, respectively, 6.3 (p = 0.025), 3.6 (p = 0.120), 5.7 (p = 0.005), and 4.9 (p = 0.017) ml/year less decline compared to the M/L and L/L pool. The associations remained significant in smokers. Siedlinski et al. (2008) concluded that their findings replicated those of Guenegou et al. (2006).
In a 15-year-old girl with heme oxygenase-1 deficiency (HMOX1D; 614034), Radhakrishnan et al. (2011) identified a homozygous arg44-to-ter (R44X) mutation in the HMOX1 gene. The mutation was identified by sequencing of the HMOX1 gene. Immunostaining for HMOX1 in a kidney biopsy from the patient showed little or no HMOX1 expression. The patient had congenital asplenia, severe hemolysis, inflammation, and nephritis, which was refractory to immunosuppressive therapy.
In a 2-year-old boy with HMOX1D, Radhakrishnan et al. (2011) identified homozygosity for the R44X mutation in the HMOX1 gene. The mutation was identified by reverse transcriptase PCR.
In a 20-month-old boy with HMOX1D, Gupta et al. (2016) identified a homozygous c.130C-T transition in exon 2 of the HMOX1 gene, resulting in an R44X substitution. The mutation was identified by sequencing of the HMOX1 gene, and the parents were shown to be mutation carriers.
In a Turkish patient, born to consanguineous parents, with heme oxygenase-1 deficiency (HMOX1D; 614034), Greil et al. (2016) identified homozygosity for a gly139-to-val (G139V) substitution in the HMOX1 gene. The mutation was identified by sequencing of the HMOX1 gene, and the parents were shown to be mutation carriers. Defective HMOX1 enzyme activity was demonstrated by reduced bilirubin synthesis in patient PBMCs. Greil et al. (2016) also found increased constitutive HMOX1 protein expression in patient PBMCs that was not increased following hemin treatment as well as gain of abnormal peroxidase function.
In a 17-month-old female, born to consanguineous Iranian parents, with heme oxygenase-1 deficiency (HMOX1D; 614034), Tahghighi et al. (2019) identified a homozygous c.610A-T transversion in exon 3 of the HMOX1 gene, resulting in a lys204-to-ter (K204X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
In a boy with heme oxygenase-1 deficiency (HMOX1D; 614034), Chau et al. (2020) identified compound heterozygous mutations in the HMOX1 gene: an insertion/deletion mutation (c.262_268delinsCC, NM_002133.2), resulting in a frameshift and premature termination (Ala88ProfsTer51), and a c.636+2T-A donor splice site mutation (141250.0008). The mutations were identified by whole-exome sequencing, and the parents were shown to be mutation carriers. HMOX1 deficiency was confirmed in patient PBMCs by Western blot analysis, which showed absence of protein expression after treatment with cobalt protoporphyrin, an inducer of HMOX1.
For discussion of the c.636+2T-A transition (c.636+2T-A, NM_002133.2) in the HMOX1 gene that was identified in compound heterozygous state in a patient with heme oxygenase-1 deficiency (HMOX1D; 614034) by Chau et al. (2020), see 141250.0008.
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