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CYB5R3 cytochrome b5 reductase 3 [ Homo sapiens (human) ]

Gene ID: 1727, updated on 7-Apr-2024

Summary

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Official Symbol
CYB5R3provided by HGNC
Official Full Name
cytochrome b5 reductase 3provided by HGNC
Primary source
HGNC:HGNC:2873
See related
Ensembl:ENSG00000100243 MIM:613213; AllianceGenome:HGNC:2873
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
B5R; DIA1
Summary
This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]
Expression
Ubiquitous expression in fat (RPKM 110.9), testis (RPKM 52.5) and 24 other tissues See more
Orthologs
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Genomic context

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Location:
22q13.2
Exon count:
12
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 22 NC_000022.11 (42617840..42649392, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 22 NC_060946.1 (43098710..43130267, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 22 NC_000022.10 (43013846..43045398, complement)

Chromosome 22 - NC_000022.11Genomic Context describing neighboring genes Neighboring gene DNA polymerase delta interacting protein 3 Neighboring gene uncharacterized LOC124905127 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43009109-43009652 Neighboring gene H3K27ac hESC enhancer GRCh37_chr22:43010197-43010740 Neighboring gene H3K27ac hESC enhancer GRCh37_chr22:43010741-43011284 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19174 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19175 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43019599-43020153 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43027517-43028018 Neighboring gene RNA, U12 small nuclear Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43032221-43032758 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43032759-43033294 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43040225-43041216 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13834 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13835 Neighboring gene H3K27ac hESC enhancer GRCh37_chr22:43045573-43046386 Neighboring gene ATP synthase membrane subunit g like Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13837 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13838 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13839 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43082077-43082968 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43082969-43083858 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43083859-43084750 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43089063-43089584 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43089979-43090480 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43090481-43090980 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43094281-43094964 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43094965-43095648 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43097017-43097700 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43098815-43099314 Neighboring gene ReSE screen-validated silencer GRCh37_chr22:43103268-43103479 Neighboring gene alpha 1,4-galactosyltransferase (P1PK blood group) Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19176 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13840 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13841 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13842 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr22:43136606-43137182 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43138337-43138912 Neighboring gene Sharpr-MPRA regulatory region 8887 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43139489-43140064 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43144579-43145140 Neighboring gene Sharpr-MPRA regulatory region 987 Neighboring gene ReSE screen-validated silencer GRCh37_chr22:43165586-43165772 Neighboring gene ribosomal protein L5 pseudogene 34

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia. Deorukhkar A, et al. Mol Biol Rep, 2022 Mar. PMID 35064402
  2. Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia. Gupta V, et al. Hum Mutat, 2020 Apr. PMID 31898843
  3. Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I. Kedar PS, et al. Hematology, 2018 Sep. PMID 29482478
  4. Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy. Fuller TD, et al. Pediatr Res, 2015 Mar. PMID 25521918, Free PMC Article
  5. Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India. Warang PP, et al. Clin Genet, 2015. PMID 24266649

See all (150) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia.
    Title: Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia.
  2. Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia.
    Title: Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia.
  3. The CYB5R3(c) (.350C>G) and G6PD A alleles modify severity of anemia in malaria and sickle cell disease.
    Title: The CYB5R3(c) (.350C>G) and G6PD A alleles modify severity of anemia in malaria and sickle cell disease.
  4. study indicated that novel homozygous mutation p.Arg192Cys in CYB5R3 gene present in eight cases and the possibility of high prevalence of heterozygous in Indian population causing Type I recessive congenital methemoglobinemia.
    Title: Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I.
  5. Data suggest that cytochrome b5 (CYB5) and cytochrome b5 reductase 3 (CYB5R3) can reduce human cytoglobin (CYGB) and zebrafish cytoglobins at rates up to 250-fold higher than those reported for the known physiological substrates, hemoglobin and myoglobin; the three proteins (CYB5+CYB5R3+CYGB) appear to constitute a metabolon involved in generation of nitric oxide.
    Title: Efficient Reduction of Vertebrate Cytoglobins by the Cytochrome b(5)/Cytochrome b(5) Reductase/NADH System.
  6. CYB5R3 promotes colonization and metastasis formation and is a prognostic marker of disease-free and overall survival in estrogen receptor-negative breast cancer.
    Title: NADH-Cytochrome b5 Reductase 3 Promotes Colonization and Metastasis Formation and Is a Prognostic Marker of Disease-Free and Overall Survival in Estrogen Receptor-Negative Breast Cancer.
  7. Variants in CYB5A and CYB5R3 should be considered in the evaluation of breast cancer risk in African American women.
    Title: Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women.
  8. Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy.
    Title: Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy.
  9. The results unveil a potential mechanism of action by which CYB5R3 deficiency contributes to the pathophysiological underpinnings of neurological disorders in RHM patients.
    Title: Membrane-bound CYB5R3 is a common effector of nutritional and oxidative stress response through FOXO3a and Nrf2.
  10. NADH-CYB5R deficiency causes two forms of recessive congenital methemoglobinemia with cyanosis.
    Title: Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India.
Submit: New GeneRIF Correction See all GeneRIFs (30)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description Tests
Deficiency of cytochrome-b5 reductase
MedGen: C0268193 OMIM: 250800 GeneReviews: Not available
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Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

HIV-1 interactions

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Protein interactions

Protein Gene Interaction Pubs
Envelope surface glycoprotein gp160, precursor env HIV-1 gp160 interacts with CYB5R PubMed

Go to the HIV-1, Human Interaction Database

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables ADP binding IEA
Inferred from Electronic Annotation
more info
  
enables AMP binding IEA
Inferred from Electronic Annotation
more info
  
enables FAD binding IBA
Inferred from Biological aspect of Ancestor
more info
  
enables FAD binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables NAD binding IEA
Inferred from Electronic Annotation
more info
  
enables cytochrome-b5 reductase activity, acting on NAD(P)H IDA
Inferred from Direct Assay
more info
 PubMed 
enables cytochrome-b5 reductase activity, acting on NAD(P)H IMP
Inferred from Mutant Phenotype
more info
 PubMed 
contributes_to nitrite reductase (NO-forming) activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in blood circulation TAS
Traceable Author Statement
more info
 PubMed 
involved_in cholesterol biosynthetic process IEA
Inferred from Electronic Annotation
more info
  
involved_in nitric oxide biosynthetic process IDA
Inferred from Direct Assay
more info
 PubMed 
Component Evidence Code Pubs
located_in azurophil granule lumen TAS
Traceable Author Statement
more info
  
located_in cytoplasm TAS
Traceable Author Statement
more info
 PubMed 
located_in endoplasmic reticulum IDA
Inferred from Direct Assay
more info
  
located_in endoplasmic reticulum membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in extracellular region TAS
Traceable Author Statement
more info
  
part_of hemoglobin complex TAS
Traceable Author Statement
more info
 PubMed 
located_in lipid droplet IDA
Inferred from Direct Assay
more info
 PubMed 
located_in membrane HDA PubMed 
located_in mitochondrial membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in mitochondrial outer membrane TAS
Traceable Author Statement
more info
  
located_in mitochondrion HDA PubMed 
is_active_in mitochondrion IBA
Inferred from Biological aspect of Ancestor
more info
  
part_of nitric-oxide synthase complex IDA
Inferred from Direct Assay
more info
 PubMed 

General protein information

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Preferred Names
NADH-cytochrome b5 reductase 3
Names
NADH-cytochrome b5 reductase 3 membrane-bound form
NADH-cytochrome b5 reductase 3 soluble form
diaphorase-1
mutant NADH-cytochrome b5 reductase
NP_000389.1
NP_001123291.1
NP_001165131.1
NP_001165132.1
NP_015565.1
XP_047297139.1
XP_054181199.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_012194.1 RefSeqGene

    Range
    5008..36560
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_000398.7 → NP_000389.1  NADH-cytochrome b5 reductase 3 isoform 1

    See identical proteins and their annotated locations for NP_000389.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) encodes the membrane-bound form (isoform 1) of the enzyme. This isoform (1) is referred to in the literature as isoform m.
    Source sequence(s)
    BC004821, BX334220, Z93241
    Consensus CDS
    CCDS33658.1
    UniProtKB/Swiss-Prot
    B1AHF2, B7Z7L3, O75675, P00387, Q8TDL8, Q8WTS8, Q9UEN4, Q9UEN5, Q9UL55, Q9UL56
    UniProtKB/TrEMBL
    A0A8J8Z3C6
    Related
    ENSP00000338461.6, ENST00000352397.10
    Conserved Domains (2) summary
    cd06183
    Location:45 → 301
    cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
    PTZ00319
    Location:11 → 301
    PTZ00319; NADH-cytochrome B5 reductase; Provisional

  2. NM_001129819.2 → NP_001123291.1  NADH-cytochrome b5 reductase 3 isoform 2

    See identical proteins and their annotated locations for NP_001123291.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) has an alternate 5' exon, as compared to variant 1. The resulting isoform (2) is the soluble form of the enzyme, which has a shorter N-terminus when it is compared to the membrane-bound form. This isoform (2) is referred to in the literature as isoform s.
    Source sequence(s)
    AJ310900, DA268749, DA548643, Z93241
    Consensus CDS
    CCDS14040.1
    UniProtKB/TrEMBL
    A0A8J8Z3C6
    Related
    ENSP00000384834.3, ENST00000407623.8
    Conserved Domains (2) summary
    cd06183
    Location:22 → 278
    cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
    PTZ00319
    Location:3 → 278
    PTZ00319; NADH-cytochrome B5 reductase; Provisional

  3. NM_001171660.2 → NP_001165131.1  NADH-cytochrome b5 reductase 3 isoform 3

    See identical proteins and their annotated locations for NP_001165131.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5) differs in the 5' UTR and 5' coding region and initiates translation at an alternate start codon, compared to variant 1. The encoded isoform (3) is longer and has a distinct N-terminus, compared to isoform 1.
    Source sequence(s)
    AK302204, Z93241
    Consensus CDS
    CCDS54535.1
    UniProtKB/TrEMBL
    A0A8J8Z3C6
    Related
    ENSP00000509015.1, ENST00000688117.1
    Conserved Domains (2) summary
    cd06183
    Location:78 → 334
    cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
    PTZ00319
    Location:44 → 334
    PTZ00319; NADH-cytochrome B5 reductase; Provisional

  4. NM_001171661.1 → NP_001165132.1  NADH-cytochrome b5 reductase 3 isoform 2

    See identical proteins and their annotated locations for NP_001165132.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) uses an alternate exon in the 5' UTR and 5' coding region, compared to variant 1. The resulting isoform (2) is the soluble form of the enzyme, which has a shorter N-terminus when it is compared to the membrane-bound form. This isoform (2) is referred to in the literature as isoform s.
    Source sequence(s)
    BM564146, Z93241
    Consensus CDS
    CCDS14040.1
    UniProtKB/TrEMBL
    A0A8J8Z3C6
    Related
    ENSP00000385679.1, ENST00000402438.6
    Conserved Domains (2) summary
    cd06183
    Location:22 → 278
    cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
    PTZ00319
    Location:3 → 278
    PTZ00319; NADH-cytochrome B5 reductase; Provisional

  5. NM_007326.4 → NP_015565.1  NADH-cytochrome b5 reductase 3 isoform 2

    See identical proteins and their annotated locations for NP_015565.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) uses an alternate exon in the 5' UTR and 5' coding region, compared to variant 1. The resulting isoform (2) is the soluble form of the enzyme, which has a shorter N-terminus when it is compared to the membrane-bound form. This isoform (2) is referred to in the literature as isoform s.
    Source sequence(s)
    AJ310900, DB029897, Z93241
    Consensus CDS
    CCDS14040.1
    UniProtKB/TrEMBL
    A0A8J8Z3C6
    Related
    ENSP00000508492.1, ENST00000687198.1
    Conserved Domains (2) summary
    cd06183
    Location:22 → 278
    cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
    PTZ00319
    Location:3 → 278
    PTZ00319; NADH-cytochrome B5 reductase; Provisional

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000022.11 Reference GRCh38.p14 Primary Assembly

    Range
    42617840..42649392 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_047441183.1 → XP_047297139.1  NADH-cytochrome b5 reductase 3 isoform X1

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060946.1 Alternate T2T-CHM13v2.0

    Range
    43098710..43130267 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054325224.1 → XP_054181199.1  NADH-cytochrome b5 reductase 3 isoform X1

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P00387.3 GenPept UniProtKB/Swiss-Prot:P00387

Gene LinkOut

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