CYB5A (Cytochrome B5 Type A (microsomal))

2015-11-01   Valentina E Gomez , Amir Avan , Godefridus J Peters , Elisa Giovannetti 

Identity

HGNC
LOCATION
18q22.3
IMAGE
Atlas Image
LEGEND
Figure 1. Localization of CYB5A on chromosome 18, q22.3. CYB5A starts from 74250847 and ends at 74292016 bp.
LOCUSID
ALIAS
CYB5,MCB5,METAG
FUSION GENES

Abstract

Review on Cytochrome B5 Type A, with data on DNA\/RNA, on the protein encoded and the diseases in which the gene has been implicated.

DNA/RNA

Description

The CYB5A gene is situated on chromosome 18, starting from 74250847 and ending at 74292016 bp. The gene encodes a membrane-bound cytochrome protein.

Transcription

For this gene, seven alternatively spliced transcript variants have been identified (CYB5A-001, -002, -003, -004, -005, -006 and -007). Variants -001, -002, -005 and -006 are transcripts encoding for a protein containing 134, 98 and 124, respectively. The remaining variants do not code for a protein product: Variant -007 is a processed transcript containing 4 exons, whereas variants -003 and -004 have retained introns.

Proteins

Description

CYB5A belongs to the cytochrome b5 family of electron transport proteins found in yeasts, plants and animals. As a product of alternative splicing, the CYB5A gene encodes three distinct protein isoforms; the 134 amino acid membrane-bound form with a predicted molecular weight of 15,3 kDa, the 98 amino acid cytoplasmic form with 11,3 kDa and a 98 residues isoform from which experimental confirmation is lacking. The membrane-bound protein is composed of a single polypeptide chain folded into two domains which are structurally independent. A non-polar fragment, able to anchor the polypeptide chain to the membrane and a polar, heme-binding fragment with catalytic activity.

Expression

The expression of cytochrome B type A seems to be highly regulated in some mammals. In rats with hypothyroidism, for instance, increased CYB5A levels have been found. Furthermore, a compound called propylthiouracil, which was used to treat hyperthyroidism triggered a similar effect, leading to a 50% increase in cytochrome B type A levels. Huang and colleagues studied the transcriptional regulation of human adrenal NClH295A cells and found that it was regulated by Sp3, SF1, GATA-6 and NF-1C, four of the five factors which also exert regulating effects on P450c17.

Function

Cytochrome B5 Type A is a hemoprotein which serves as an electron carrier in various biochemical reactions. Its most important function is the NADPH-dependent reduction of methemoglobin to ferrous hemoglobin, a factor required for stearyl-CoA-desaturase activity. Morevoer, cytochrome B5 Type A participates in fatty acid desaturation, sterol metabolism and cytochrome P450-catalyzed reactions.

Homology

The CYB5A gene is conserved in Rhesus monkey, chimpanzee, cow, dog, rat, mouse, chicken, frog, mosquito, fruit fly, C. elegans, rice and A. thaliana.

Mutations

Germinal

A homozygous splice site mutation in the CYB5A gene in a patient with type IV hereditary methemoglobinemia was identified by Steggles and colleagues. The group isolated mRNA from reticulocytes and leukocytes from the patient and analyzed the CYB5A cDNA sequences by DNA sequencing. They found a 16-bp deletion in the cDNA which led to a new in-frame termination codon, thereby producing a truncated protein of 45 amino acid residues. Genomic DNA analysis revealed an AG-to-GC modification in the consensus 3 splicing junction of intron 1. The presence of this modification renders the splicing machinery to make use of the nearest AG in exon 2 as an alternative splice site, resulting in a 16-bp deletion in the mRNA.

Somatic

Additionally, a survey in the COSMIC mutation database (accession date: 6 November 6, 2015) revealed a total of 24 mutations present in different human tumors.

CDS Mutation

AA Mutation

Tissue

c.375G>C

p.L125F

Urinary tract

c.369C>T

p.V123V

Haematopoietic and lymphoid

c.14C>T

p.S5L

Haematopoietic and lymphoid

c.232A>C

p.T78P

Breast

c.172G>A

p.D58N

Breast

c.45G>A

p.E15E

Breast

c.48G>T

p.E16D

Large intestine

c.31T>C

p.Y11H

Large intestine

c.366C>T

p.A122A

Endometrium

c.138T>C

p.G46G

Kidney

c.117A>T

p.K39N

Liver

c.375G>C

p.L125F

Lung

c.245 246GG>TT

p.G82>?

Lung

c.100G>T

p.V34L

Upper aerodisgestive tract

c.7G>C

p.E3Q

Oesophagus

c.382C>T

R128C

Skin

c.256C>T

p.P86S

Skin

c.227C>T

p.S76F

Skin

c.339G>A

p.W113*

Skin

c.367G>C

p.V123L

Stomach

c.383G>A

p.R128H

Stomach

c.22G>A

p.A8T

Stomach

c.181G>C

p.E61Q

Thyroid

c.382C>T

p.R128C

Skin


Table 1. CYB5A mutations present in distinct types of tumors. The table includes the DNA modification (CDS Mutation), protein modification (AA Mutation), tissue and type of mutation (c.369C>T; c.45G>A; c.366C>T; c.138T>C: Substitution-coding silent, c.339G>A: Substitution-nonsense, c.245 246GG>TT: Complex, other: Substitution-missense).

Implicated in

Entity name
Breast cancer
Note
The effects of cytochrome b5 on breast cancer remain unclear. A proteomic approach addressed by Neubauer and collaborators found differences in the cytochrome b5 levels of sensitive to tamoxifen (ER+/PR+) and less sensitive (ER+/PR-) mammary tumor specimens. The ER+/PR+ samples exhibited decreased levels of cytochrome b5 and this lead the group to suggest that the differential susceptibility against tamoxifen might, in part be explained, as a result of aberrant cytochrome b5-dependent metabolism.
Entity name
Pancreatic cancer
Note
CYB5A has been recently identified as a prognostic factor for Pancreatic Cancer Adenocarcinoma (PDAC). Giovannetti and collaborators performed comparative genomic hybridization studies in resected patients and found a significant correlation between decreased survival and the loss of the cytoband 18q22.3, where CYB5A is located. Analysis of mRNA and protein levels of other cohorts revealed the prognostic value of CYB5A: decreased CYB5A expression levels were associated with shorter survival. In vivo orthotopic models with patient-derived CYB5A+ cells showed a significant reduction in tumor size coupled with increased survival compared to the controls. Interestingly, additional gain- and loss-of function studies performed by the group revealed a novel role of CYB5A, namely, autophagy induction.
Entity name
Hepatocellular carcinoma (HCC)
Note
Lee and collaborators addressed a proteomic approach in order to identify novel biomarkers in resected tumor and adjacent non-malignant tissue samples of 80 HCC patients. This study revealed that CYB5A significantly correlated with serum AFP, a biomarker commonly used for HCC surveillance. Moreover they suggested that its decreased levels might be a result of the disruption of the membrane-bound polysome attachment, which is required for cytochrome b5 type A synthesis.
Entity name
Lung squamous cell carcinoma
Note
Sriram and colleagues analyzed 62 primary lung SCCs (28 with recurrence and 34 with no evidence of recurrence) using a whole-genome aCGH microarray to identify genomic copy number alterations specific to tumors. They identified CYB5A among prognostic genes that had lower copy number in the lung SCC of patients who recurred (Sriram et al., 2012). Moreover, they demonstrated association of the reduced copy number and mRNA expression of SOCS6 with disease recurrence in SCC patients.
Entity name
Ovarian cancer
Note
Cortesi et al., performed a comparative proteomic study on biopsies from six consecutive patients with endometrioid or serous ovarian carcinoma who had not been previously treated with chemotherapy prior to surgical resection, in order to recognize potential biomarkers. They identified CYB5A among the proteins separated by 2-DE electrophoresis and detected by MS analysis.
Entity name
Colorectal tumors
Note
Agostini and collaborators evaluated the value of ten markers including CYB5A (D18S58) in 44 CRC patients, who underwent surgery using a multiplex PCR assay for a rapid and proper classification of tumor microsatellite instability (MSI)-H, MSI-L and MSS. They revealed that a complete panel of these markers could allow the accurate evaluation of tumor MSI status in CRC patients, supporting further investigations on the prognostic value of CYB5A and other markers in management of CRC patients.
Entity name
Gastric Cancer
Note
Nair and colleagues carried out gene expression analysis in Singapore and UK Gastric cancer datasets using GeneSpring. This study showed the upregulation of CYB5A in the Singapores Population (Nair et al., 2014).
Entity name
Rheumatoid arthritis (RA)
Note
RA is characterized by decreased androgens levels and CYB5A acts as a cofactor of one of the two enzymes responsible for de novo androgens synthesis, cytochrome P450 17A1 (17,20-lyase). For this reason, Stark and collaborators analyzed the presence of Single Nucleotide Polymorphisms (SNPs) in the CYB5A gene in two published RA Genome Wide Association Study (GWAS) datasets. Subsequently, cytochrome b5 expression analyses as well as androgen production after steroid conversion were evaluated in candidate SNPs from a RA case-control study. Among the most important findings was the identification of a SNP in CYB5A, designated as rs1790834, which was associated to decreased risk of RA. The group suggested that rs1790834 might exert its protective effects by increasing the capacity of androgen synthesis.
Entity name
Type 2 diabetes and adiposity
Note
Huang and colleagues performed whole exome sequencing in order to identify potential functional coding variants affecting metabolic processes associated with increased risk of type 2 diabetes. Their analyses revealed a SNP in CYB5A, designated as rs7238987, which was significantly associated with pre-diabetic traits such as Percentage Body Fat (PFAT) and Body Mass Index (BMI). All together, the group identified a potential new locus for adiposity and higher risk of type 2 diabetes. Nevertheless, functional studies validating these results are still lacking.
Entity name
Cushing Syndrome
Note
The effects of cytochrome b5 on cytochrome P450 17A1 have been shown by distinct research groups. Since Cushings syndrome is characterized by abnormalities in the production of cortisol and adrenal androgens, the expression levels and activity of cytochrome b5 in this condition have also been evaluated. Sakai and colleagues performed in vitro biochemical assays on adrenocortical adenoma tissue from Cushins syndrome patients and found high levels of cytochrome b5, which correlated with higher 17,20-lyase activity. Moreover, an immunohistochemical study performed by Yanase and collaborators revealed high cytochrome b5 levels in all adrenocortical layers in adrenal glands, with a particularly intense immunoreactivity in the zona reticularis, providing evidence for the functional association between cytochrome b5 type A and the production of adrenal androgens.

Bibliography

Pubmed IDLast YearTitleAuthors
201645412010A ten markers panel provides a more accurate and complete microsatellite instability analysis in mismatch repair-deficient colorectal tumors.Agostini M et al
255161342015Differential expression of CYB5A in Chinese and European pig breeds due to genetic variations in the promoter region.Bai Y et al
264084192015Unraveling the complexity of autophagy: Potential therapeutic applications in Pancreatic Ductal Adenocarcinoma.Gómez VE et al
81688361994A splicing mutation in the cytochrome b5 gene from a patient with congenital methemoglobinemia and pseudohermaphrodism.Giordano SJ et al
241512002014Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes.Huang K et al
158315262005Regulation of cytochrome b5 gene transcription by Sp3, GATA-6, and steroidogenic factor 1 in human adrenal NCI-H295A cells.Huang N et al
221707102012A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency.Idkowiak J et al
262358152015Photo-initiated crosslinking extends mapping of the protein-protein interface to membrane-embedded portions of cytochromes P450 2B4 and b₅.Ječmen T et al
126674902003The membrane-interactive tail of cytochrome b(5) can function as a stop-transfer sequence in concert with a signal sequence to give inversion of protein topology in the endoplasmic reticulum.Kaderbhai MA et al
261243372015Ataxia-Telangiectasia and RAD3-Related and Ataxia-Telangiectasia-Mutated Proteins in Epithelial Ovarian Carcinoma: Their Expression and Clinical Significance.Lee B et al
191613262009Proteomic expression signature distinguishes cancerous and nonmalignant tissues in hepatocellular carcinoma.Lee NP et al
166459502006Breast cancer proteomics by laser capture microdissection, sample pooling, 54-cm IPG IEF, and differential iodine radioisotope detection.Neubauer H et al
81375191994In-vitro evidence for the regulation of 17,20-lyase activity by cytochrome b5 in adrenocortical adenomas from patients with Cushing's syndrome.Sakai Y et al
223634342012Array-comparative genomic hybridization reveals loss of SOCS6 is associated with poor prognosis in primary lung squamous cell carcinoma.Sriram KB et al
258903142015CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women.Stark K et al
239899722013Probing the transmembrane structure and topology of microsomal cytochrome-p450 by solid-state NMR on temperature-resistant bicelles.Yamamoto K et al
96254511998Immunohistochemical study of cytochrome b5 in human adrenal gland and in adrenocortical adenomas from patients with Cushing's syndrome.Yanase T et al

Other Information

Locus ID:

NCBI: 1528
MIM: 613218
HGNC: 2570
Ensembl: ENSG00000166347

Variants:

dbSNP: 1528
ClinVar: 1528
TCGA: ENSG00000166347
COSMIC: CYB5A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000166347ENST00000299438J3KNC7
ENSG00000166347ENST00000340533P00167
ENSG00000166347ENST00000340533A0A384ME44
ENSG00000166347ENST00000397914P00167
ENSG00000166347ENST00000494131P00167

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
MetabolismREACTOMER-HSA-1430728
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Metabolism of water-soluble vitamins and cofactorsREACTOMER-HSA-196849
Vitamin C (ascorbate) metabolismREACTOMER-HSA-196836

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA27331CYB5R3GenePathwayassociated23913015

References

Pubmed IDYearTitleCitations
205112332010Nitric-oxide dioxygenase function of human cytoglobin with cellular reductants and in rat hepatocytes.34
156874932005Regulation of 17,20 lyase activity by cytochrome b5 and by serine phosphorylation of P450c17.29
200808432010Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X.27
149852522004Colocalization of P450c17 and cytochrome b5 in androgen-synthesizing tissues of the human.25
221707102012A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency.22
166793162006Identification of the interactions between cytochrome P450 2E1 and cytochrome b5 by mass spectrometry and site-directed mutagenesis.21
199970422010Cytochrome b5 and NADH cytochrome b5 reductase: genotype-phenotype correlations for hydroxylamine reduction.20
182993242008Cytochrome b5, not superoxide anion radical, is a major reductant of indoleamine 2,3-dioxygenase in human cells.19
158315262005Regulation of cytochrome b5 gene transcription by Sp3, GATA-6, and steroidogenic factor 1 in human adrenal NCI-H295A cells.18
173207572007Reduction of hexavalent chromium by human cytochrome b5: generation of hydroxyl radical and superoxide.16

Citation

Valentina E Gomez ; Amir Avan ; Godefridus J Peters ; Elisa Giovannetti

CYB5A (Cytochrome B5 Type A (microsomal))

Atlas Genet Cytogenet Oncol Haematol. 2015-11-01

Online version: http://atlasgeneticsoncology.org/gene/53723/cyb5a