GeneBe

HMOX1

protein-coding

heme oxygenase 1

Gene summary

Heme oxygenase, an essential enzyme in heme catabolism, cleaves heme to form biliverdin, which is subsequently converted to bilirubin by biliverdin reductase, and carbon monoxide, a putative neurotransmitter. Heme oxygenase activity is induced by its substrate heme and by various nonheme substances. Heme oxygenase occurs as 2 isozymes, an inducible heme oxygenase-1 and a constitutive heme oxygenase-2. HMOX1 and HMOX2 belong to the heme oxygenase family. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002133.3

Inheritance

AR

ClinVar variants

P:26U:96B:129

Top phenotype

Heme oxygenase 1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr22:35,380,361-35,394,214

External References & Databases

Ensembl (ENSG00000100292)NCBI Gene (3162)OMIM (141250)HGNC:5013GenCCUniProt (P09601)AlphaFoldClinVar (HMOX1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~13.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

heme oxygenase 1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013536

Submitter: Orphanet

heme oxygenase 1 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013536

Submitter: Ambry Genetics

heme oxygenase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013536

Submitter: PanelApp Australia

heme oxygenase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013536

Submitter: Labcorp Genetics (formerly Invitae)

heme oxygenase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013536

Submitter: ClinGen

HMOX1 was first reported in relation to autosomal recessive heme oxygenase deficiency in 1999 (Yachie et al., PMID: 9884342). The primary features of this condition include recurrent fever, hemolytic anemia, low serum bilirubin, elevated serum ferritin, and small or absent spleen. The underlying mechanism is a loss of heme oxidase activity leading to increased susceptibility to oxidative damage (PMID: 20055707). Six variants (nonsense, frameshift, splice site, whole exon deletion) that have been reported in five probands in five publications (PMIDs: 9884342; 210818618; 26526137; 32587840; 33066778) are included in this curation. Co-segregation with disease has not been observed. The mechanism of pathogenicity is biallelic loss of function. This gene-disease association is also supported by the known biological function of HMOX1, its expression pattern, functional alterations in patient and non-patient cells, and a non-human animal model (PMIDs: 9380735; 9380736; 9884342; 20055707; 25613900). In summary, HMOX1 is definitively associated with autosomal recessive heme oxygenase deficiency 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on 12/18/2023 (SOP Version 10).

chronic obstructive pulmonary diseaseLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0005002

Submitter: Labcorp Genetics (formerly Invitae)

cystic fibrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: Orphanet

Clinical Genomic Database (CGD)

Heme oxygenase 1 deficiencyAR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Renal

Intervention: Allergy/Immunology/Infectious; Hematologic

Rationale: Although the disease may ultimately be fatal, the condition includes immunodeficiency (includind due to asplenia), and prophylaxis and prompt and aggressive treatment of infections may be beneficial; RBC transfusions may be indicated for anemia

Refs: 9884342; 21088618; 22023467Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HMOX1 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 285
not specifiedTotal: 38
Heme oxygenase 1 deficiencyTotal: 10
HMOX1-related disorderTotal: 9
Chronic obstructive pulmonary diseaseTotal: 2
COPD, severe early onsetTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002133.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
122
clinvar
 123
missense
1
clinvar
1
clinvar
95
clinvar
5
clinvar
2
clinvar
 104
nonsense
7
clinvar
2
clinvar
 9
start loss
0
frameshift
9
clinvar
2
clinvar
 11
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
 4
Total188961272251

Highest pathogenic variant AF is 0.0000514221

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002133.3RefSeqNP_002124.15MANE Select
ENST00000216117.9EnsemblENSP00000216117.85MANE Select
ENST00000412893.5EnsemblENSP00000413316.13Standard
ENST00000481190.2EnsemblENSP00000503987.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
hmox1aDanio rerio

Structure: cardiac ventricle

Quality: increased volume

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • HIF-1 signaling pathway - Homo sapiens (human)
  • Hepatocellular carcinoma - Homo sapiens (human)
  • Fluid shear stress and atherosclerosis - Homo sapiens (human)
  • Porphyrin and chlorophyll metabolism - Homo sapiens (human)
  • Mineral absorption - Homo sapiens (human)

Biological Process

  • angiogenesis
  • endothelial cell proliferation
  • wound healing involved in inflammatory response
  • negative regulation of leukocyte migration
  • heme oxidation

Molecular Function

  • heme oxygenase (decyclizing) activity
  • phospholipase D activity
  • protein binding
  • enzyme binding
  • heme binding

Cellular Component

  • extracellular space
  • nucleus
  • nucleolus
  • endoplasmic reticulum
  • endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000216117
Coding exons
5
Length
13854
Individuals with no LoFs
125726
Homozygous LoFs
0
Heterozygous LoFs
22
Defined
125748
p
0.0000875
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.5201901711.110.00001111860
Missense (PolyPhen)6353.1131.1862663
Synonymous-0.9557968.91.150.00000400595
Loss of Function1.75511.30.4415.84e-7126

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000590.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.000170.00017rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed. Exhibits cytoprotective effects since excess of free heme sensitizes cells to undergo apoptosis.;
Disease
DISEASE: Heme oxygenase 1 deficiency (HMOX1D) [MIM:614034]: A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly. {ECO:0000269|PubMed:9884342}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.862

Intolerance Scores

LoFtool
0.611
RVIS EVS
-0.6
RVIS percentile EVS
17.91

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.999

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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