NCF4 neutrophil cytosolic factor 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: NCF4provided by HGNC
Official Full Name: neutrophil cytosolic factor 4provided by HGNC
Primary source: HGNC:HGNC:7662
See related: Ensembl:ENSG00000100365 MIM:601488; AllianceGenome:HGNC:7662
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: NCF; CGD3; P40PHOX; SH3PXD4
Summary: The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]
Expression: Biased expression in bone marrow (RPKM 51.6), appendix (RPKM 18.9) and 11 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 22q12.3

Exon count:: 12

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	22	NC_000022.11 (36861006..36878015)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	22	NC_060946.1 (37316866..37336974)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	22	NC_000022.10 (37257048..37274057)

Chromosome 22 - NC_000022.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

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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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Polymorphisms of the NCF4 Gene Increase the Risk of Chronic Heart Failure in Patients with Type 2 Diabetes Mellitus.
Title: Polymorphisms of the NCF4 Gene Increase the Risk of Chronic Heart Failure in Patients with Type 2 Diabetes Mellitus.
NCF1/2/4 Are Prognostic Biomarkers Related to the Immune Infiltration of Kidney Renal Clear Cell Carcinoma.
Title: NCF1/2/4 Are Prognostic Biomarkers Related to the Immune Infiltration of Kidney Renal Clear Cell Carcinoma.
Association of NCF2, NCF4, and CYBA Gene Polymorphisms with Rheumatoid Arthritis in a Chinese Population.
Title: Association of NCF2, NCF4, and CYBA Gene Polymorphisms with Rheumatoid Arthritis in a Chinese Population.
We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another.
Title: Inherited p40phox deficiency differs from classic chronic granulomatous disease.
Tyrosine kinase substrate (Tks) proteins, analogous to the related proteins p47(phox), p40(phox) and NoxO1, also facilitate local generation of reactive oxygen species (ROS), which aid in signaling at invadopodia and/or podosomes to promote their activity. As their name suggests, Tks adaptor proteins are substrates for tyrosine kinases, especially Src. [review]
Title: Tks adaptor proteins at a glance.
Phosphoinositol 3-phosphate regulates reactive oxygen species production by maintaining p40phox and p67phox at the phagosomal membrane.
Title: Phosphoinositol 3-phosphate acts as a timer for reactive oxygen species production in the phagosome.
NCF4 polymorphism was associated with Crohn's disease, but not ulcerative colitis in Caucasian--{REVIEW}
Title: Association between NCF4 rs4821544T/C polymorphism and inflammatory bowel disease risk in Caucasian: a meta-analysis.
NCF4 may induce ex- pression of NADPH oxidase enzymes, such as p67phox, p47phox, p22phox and NOX2, which lead to increased ROS levels.
Title: Activation of NADPH oxidase subunit NCF4 induces ROS-mediated EMT signaling in HeLa cells.
Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer.
Title: Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer.
The contribution of the functionally relevant NADPH polymorphisms rs1883112 and rs4673 to anthracycline-related heart lesions provides a plausible explanation for their modulation of cardiotoxicity.
Title: Association of anthracycline-related cardiac histological lesions with NADPH oxidase functional polymorphisms.

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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
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 MedGen: C3151409 OMIM: 613960 GeneReviews: Chronic Granulomatous Disease	Compare labs

EBI GWAS Catalog

Description
Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH47220 (e-PCR)
- UniSTS:75020

RH66798 (e-PCR)
- UniSTS:51632

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables phosphatidylinositol-3-phosphate binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables superoxide-generating NADPH oxidase activator activity	IBA Inferred from Biological aspect of Ancestor more info
enables superoxide-generating NADPH oxidase activator activity	IMP Inferred from Mutant Phenotype more info	PubMed

Process	Evidence Code	Pubs
involved_in phagocytosis	IEA Inferred from Electronic Annotation more info
involved_in respiratory burst	NAS Non-traceable Author Statement more info	PubMed
involved_in superoxide anion generation	IBA Inferred from Biological aspect of Ancestor more info
involved_in superoxide anion generation	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
part_of NADPH oxidase complex	IBA Inferred from Biological aspect of Ancestor more info
part_of NADPH oxidase complex	IDA Inferred from Direct Assay more info	PubMed
part_of NADPH oxidase complex	NAS Non-traceable Author Statement more info	PubMed
is_active_in cytoplasm	IBA Inferred from Biological aspect of Ancestor more info
located_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
located_in endosome membrane	IDA Inferred from Direct Assay more info	PubMed
located_in membrane	IDA Inferred from Direct Assay more info	PubMed
located_in phagolysosome	TAS Traceable Author Statement more info
located_in plasma membrane	NAS Non-traceable Author Statement more info	PubMed

General protein information

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Preferred Names: neutrophil cytosol factor 4

Names: NCF-4; SH3 and PX domain-containing protein 4; neutrophil NADPH oxidase factor 4; neutrophil cytosolic factor 4, 40kDa; p40-phox

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

NG_023400.1 RefSeqGene

Range

5001..22030

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GenBank, FASTA, Sequence Viewer (Graphics), LRG_159

mRNA and Protein(s)

NM_000631.5 → NP_000622.2 neutrophil cytosol factor 4 isoform 1

See identical proteins and their annotated locations for NP_000622.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) lacks an internal coding segment compared to variant 2, which leads to a translation frameshift. The resulting isoform (1) has a distinct and shorter C-terminus, as compared to isoform 2.

Source sequence(s)

BC002798, BU076892, BX355636

Consensus CDS

CCDS13934.1

UniProtKB/Swiss-Prot

A8K4F9, O60808, Q15080, Q86U56, Q9BU98, Q9NP45

UniProtKB/TrEMBL

Q53FG4, Q6FGM9

Related

ENSP00000248899.6, ENST00000248899.11

Conserved Domains (3) summary

cd06399
Location:238 → 329

PB1_P40; The PB1 domain is essential part of the p40 adaptor protein which plays an important role in activating phagocyte NADPH oxidase during phagocytosis. The PB1 domain is a modular domain mediating specific protein-protein interaction which play a role in ...

cd06882
Location:19 → 141

PX_p40phox; The phosphoinositide binding Phox Homology domain of the p40phox subunit of NADPH oxidase

cd11869
Location:174 → 227

SH3_p40phox; Src Homology 3 domain of the p40phox subunit of NADPH oxidase
NM_013416.4 → NP_038202.2 neutrophil cytosol factor 4 isoform 2

See identical proteins and their annotated locations for NP_038202.2

Status: REVIEWED

Description

Transcript Variant: This variant (2) represents the longer transcript and encodes the longer isoform (2). This isoform (2) lacks the PC (Phox and Cdc24p) motif, which may be important for the interaction with NCF2.

Source sequence(s)

AK290924, BC002798

Consensus CDS

CCDS13935.1

UniProtKB/TrEMBL

A0A217FLJ2

Related

ENSP00000380334.4, ENST00000397147.7

Conserved Domains (3) summary

cd06882
Location:19 → 141

PX_p40phox; The phosphoinositide binding Phox Homology domain of the p40phox subunit of NADPH oxidase

cd11869
Location:174 → 227

SH3_p40phox; Src Homology 3 domain of the p40phox subunit of NADPH oxidase

cl02720
Location:238 → 258

PB1; The PB1 domain is a modular domain mediating specific protein-protein interactions which play a role in many critical cell processes, such as osteoclastogenesis, angiogenesis, early cardiovascular development, and cell polarity. A canonical PB1-PB1 ...

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

NC_000022.11 Reference GRCh38.p14 Primary Assembly

Range

36861006..36878015

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_047441385.1 → XP_047297341.1 neutrophil cytosol factor 4 isoform X2
XM_047441384.1 → XP_047297340.1 neutrophil cytosol factor 4 isoform X1

Reference GRCh38.p14 ALT_REF_LOCI_1

Genomic

NT_187631.1 Reference GRCh38.p14 ALT_REF_LOCI_1

Range

81800..101331

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GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

NC_060946.1 Alternate T2T-CHM13v2.0

Range

37316866..37336974

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054325654.1 → XP_054181629.1 neutrophil cytosol factor 4 isoform X5

UniProtKB/TrEMBL

A0A494BZS1
XM_054325656.1 → XP_054181631.1 neutrophil cytosol factor 4 isoform X6
XM_054325653.1 → XP_054181628.1 neutrophil cytosol factor 4 isoform X4
XM_054325655.1 → XP_054181630.1 neutrophil cytosol factor 4 isoform X5

UniProtKB/TrEMBL

A0A494BZS1
XM_054325651.1 → XP_054181626.1 neutrophil cytosol factor 4 isoform X3
XM_054325652.1 → XP_054181627.1 neutrophil cytosol factor 4 isoform X1