COX4I2

Summary

COX4I2 (cytochrome c oxidase subunit 4I2, HGNC:16232) is a protein-coding gene on chromosome 20q11.21, encoding Cytochrome c oxidase subunit 4 isoform 2, mitochondrial (Q96KJ9). Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation.

Source: NCBI Gene 84701 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pancreatic insufficiency-anemia-hyperostosis syndrome (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 90 total
• Phenotypes (HPO): 19
• MANE Select transcript: NM_032609

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16232
Approved symbol	COX4I2
Name	cytochrome c oxidase subunit 4I2
Location	20q11.21
Locus type	gene with protein product
Status	Approved
Aliases	COXIV-2, COX4B, dJ857M17.2, COX4-2
Ensembl gene	ENSG00000131055
Ensembl biotype	protein_coding
OMIM	607976
Entrez	84701

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000376075, ENST00000490030, ENST00000890502, ENST00000890503, ENST00000948152, ENST00000948153

RefSeq mRNA: 1 — MANE Select: NM_032609 NM_032609

CCDS: CCDS13187

Canonical transcript exons

ENST00000376075 — 5 exons

Exon	Start	End
ENSE00000898442	31643404	31643535
ENSE00001048763	31637912	31637962
ENSE00001469327	31644768	31645006
ENSE00003473045	31639018	31639099
ENSE00003503773	31639933	31640097

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 95.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7432 / max 89.5498, expressed in 181 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183977	0.5689	167
183976	0.1743	84

Top tissues by expression

233 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	95.84	gold quality
right lung	UBERON:0002167	94.95	gold quality
upper lobe of left lung	UBERON:0008952	91.99	gold quality
upper lobe of lung	UBERON:0008948	91.46	gold quality
oocyte	CL:0000023	89.13	gold quality
heart left ventricle	UBERON:0002084	89.04	gold quality
cardiac ventricle	UBERON:0002082	88.63	gold quality
placenta	UBERON:0001987	88.10	gold quality
right atrium auricular region	UBERON:0006631	88.07	gold quality
cardiac atrium	UBERON:0002081	87.40	gold quality
heart	UBERON:0000948	86.19	gold quality
lung	UBERON:0002048	86.13	gold quality
omental fat pad	UBERON:0010414	85.83	gold quality
peritoneum	UBERON:0002358	85.78	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.21	gold quality
kidney epithelium	UBERON:0004819	84.11	gold quality
pancreatic ductal cell	CL:0002079	83.95	silver quality
subcutaneous adipose tissue	UBERON:0002190	83.95	gold quality
left ventricle myocardium	UBERON:0006566	83.75	silver quality
right lobe of thyroid gland	UBERON:0001119	83.54	gold quality
lower lobe of lung	UBERON:0008949	83.50	gold quality
left lobe of thyroid gland	UBERON:0001120	83.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.10	gold quality
myocardium	UBERON:0002349	82.54	silver quality
gall bladder	UBERON:0002110	82.37	gold quality
thyroid gland	UBERON:0002046	82.21	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.80	gold quality
lower esophagus	UBERON:0013473	81.76	gold quality
adipose tissue	UBERON:0001013	81.41	gold quality
gingival epithelium	UBERON:0001949	81.39	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	2120.48
E-MTAB-6308	yes	1278.46
E-MTAB-8221	yes	1031.99
E-HCAD-11	yes	29.35
E-MTAB-8410	yes	17.69
E-GEOD-134144	yes	13.11
E-CURD-46	yes	11.99
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA3, HIF1A

Literature-anchored findings (GeneRIF, showing 9)

• COX4I2 is expressed in the highly oxygenated lung tissue. It is found in all cell types of the lung. (PMID:11311561)
• COX4I2 is regulated by a novel oxygen sensitive promoter element (5’-GGACGTTCCCACG-3’) conserved in mammals. Gene activity is maximal at 4% oxygen. Lung cytochrome c oxidase (COX) is 2.5 fold more active compared to liver COX, which lacks COX4I2. (PMID:17937768)
• Mutation analysis of COX4I2 is warranted in patients with malabsorption due to exocrine pancreatic insufficiency and in patients with dyserythropoeitic anemia. (PMID:19268275)
• Identification of three transcription factors that bind a conserved responsive element of the COX4I2 gene, namely recombination signal sequence-binding protein Jkappa (RBPJ), coiled-coil-helix-coiled-coil-helix domain 2 (CHCHD2) and CXXC finger protein 5 (CXXC5). (PMID:23303788)
• COX4I2 and PLAT were highly correlated with blood supply in adrenal pheochromocytoma which contribute to angiogenesis in adrenal pheochromocytoma, which could be used as biomarkers to better indicate tumor angiogenesis (PMID:31106414)
• Upregulation of COX4-2 via HIF-1alpha in Mitochondrial COX4-1 Deficiency. (PMID:33672589)
• Identification of COX4I2 as a hypoxia-associated gene acting through FGF1 to promote EMT and angiogenesis in CRC. (PMID:36064310)
• The ratio of cytochrome c oxidase subunit 4 isoform 4I1 and 4I2 mRNA is changed in permanent atrial fibrillation. (PMID:38149324)
• HIF1A transcriptional regulation of COX4I2 impacts angiogenesis in pheochromocytoma. (PMID:38422899)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cox4i2	ENSDARG00000022509
mus_musculus	Cox4i2	ENSMUSG00000009876
rattus_norvegicus	Cox4i2	ENSRNOG00000007827
drosophila_melanogaster	COX4	FBGN0032833
drosophila_melanogaster	COX4L	FBGN0033020
caenorhabditis_elegans	cox-4	WBGENE00012354

Paralogs (1): COX4I1 (ENSG00000131143)

Protein

Protein identifiers

Cytochrome c oxidase subunit 4 isoform 2, mitochondrial — Q96KJ9 (reviewed: Q96KJ9)

Alternative names: Cytochrome c oxidase subunit IV isoform 2

All UniProt accessions (2): Q96KJ9, H6SG14

UniProt curated annotations — full annotation on UniProt →

Function. Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.

Subunit / interactions. Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and COXFA4, which are encoded in the nuclear genome. The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)).

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Highly expressed in lung.

Disease relevance. Exocrine pancreatic insufficiency dyserythropoietic anemia and calvarial hyperostosis (EPIDACH) [MIM:612714] Patients present with pancreatic insufficiency, intestinal malabsorption, failure to thrive, and anemia soon after birth. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Energy metabolism; oxidative phosphorylation.

Similarity. Belongs to the cytochrome c oxidase IV family.

RefSeq proteins (1): NP_115998* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004203	Cyt_c_oxidase_su4_fam	Family
IPR013288	Cyt_c_oxidase_su4	Family
IPR036639	Cyt_c_oxidase_su4_sf	Homologous_superfamily

Pfam: PF02936

UniProt features (8 total): topological domain 2, sequence variant 2, transit peptide 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96KJ9-F1	80.84	0.53

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-611105	Respiratory electron transport
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 121 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_ELECTRON_TRANSPORT_CHAIN, KEGG_HUNTINGTONS_DISEASE, GOCC_MITOCHONDRIAL_ENVELOPE, HIF1_Q3, chr20q11, GOBP_CELLULAR_RESPIRATION, KEGG_ALZHEIMERS_DISEASE, TGGAAA_NFAT_Q4_01, GOCC_CYTOCHROME_COMPLEX, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (4): generation of precursor metabolites and energy (GO:0006091), mitochondrial electron transport, cytochrome c to oxygen (GO:0006123), cellular respiration (GO:0045333), oxidative phosphorylation (GO:0006119)

GO Molecular Function (0):

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), respiratory chain complex IV (GO:0045277), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Transcriptional Regulation by TP53	1
Aerobic respiration and respiratory electron transport	1
Cellular response to chemical stress	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrial envelope	2
metabolic process	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
energy derivation by oxidation of organic compounds	1
aerobic respiration	1
proton motive force-driven ATP synthesis	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
organelle envelope lumen	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1
cellular anatomical structure	1
mitochondrion	1
organelle membrane	1

Protein interactions and networks

STRING

1740 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX4I2	EMC8	O43402	949
COX4I2	COX5A	P20674	894
COX4I2	COX5B	P10606	869
COX4I2	COX6A1	P12074	798
COX4I2	UQCRH	P07919	796
COX4I2	MT-CO1	P00395	790
COX4I2	COX6A2	Q02221	788
COX4I2	COX6B1	P14854	786
COX4I2	SDHA	P31040	767
COX4I2	UQCRC2	P22695	741
COX4I2	COX7A1	P24310	731
COX4I2	COX8A	P10176	710
COX4I2	COX15	Q7KZN9	672
COX4I2	NDUFA9	Q16795	663
COX4I2	CYCS	P00001	657

IntAct

5 interactions, top by confidence:

A	B	Type	Score
COX4I2	GOLGB1	psi-mi:“MI:0915”(physical association)	0.400
COX4I2	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
COX4I2	H2BC12L	psi-mi:“MI:0915”(physical association)	0.400
COX4I2	COX7A2L	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): COX4I2 (Synthetic Lethality), COX4I2 (Affinity Capture-Western), COX4I2 (Proximity Label-MS), COX4I2 (Proximity Label-MS), COX4I2 (Proximity Label-MS), COX6A1 (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), UQCRQ (Affinity Capture-MS), CYCS (Reconstituted Complex), CYCS (Reconstituted Complex), CYCS (Reconstituted Complex), CYCS (Reconstituted Complex), TRPC4AP (Affinity Capture-MS), MTHFR (Affinity Capture-MS), SACM1L (Affinity Capture-MS)

ESM2 similar proteins: O13082, O13085, O46577, O46578, O46579, O46580, O46581, O46584, O46585, O46586, O64725, P00423, P06810, P07471, P10817, P10818, P10888, P12074, P13073, P13183, P19783, P24311, P32799, P43023, P43024, P56393, P80431, P80971, Q02221, Q08CE7, Q0MQC7, Q20779, Q28ED6, Q4R648, Q5R9K2, Q5RC38, Q5RK28, Q5XG64, Q810Q5, Q8TF08

Diamond homologs: O46577, O46578, O46579, O46580, O46581, O46582, O46584, O46585, O46586, O46587, O46588, O46589, O46590, P00423, P10888, P13073, P19783, P80971, Q91W29, Q91Y94, Q95283, Q96KJ9, Q9I8U0, Q9TTT8, O74988, O93980, P00424, P00425, P06810

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

90 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	20
Benign	14

Top pathogenic / likely-pathogenic (0)

SpliceAI

886 predictions. Top by Δscore:

Variant	Effect	Δscore
20:31639929:GCAGC:G	acceptor_loss	1.0000
20:31639930:CAGC:C	acceptor_loss	1.0000
20:31639931:A:AG	acceptor_gain	1.0000
20:31639931:AGCC:A	acceptor_loss	1.0000
20:31639931:AGCCC:A	acceptor_gain	1.0000
20:31639932:G:GA	acceptor_gain	1.0000
20:31639932:GCCC:G	acceptor_gain	1.0000
20:31639932:GCCCG:G	acceptor_gain	1.0000
20:31640059:G:T	donor_gain	1.0000
20:31640093:GGCCT:G	donor_gain	1.0000
20:31640094:GCCTG:G	donor_gain	1.0000
20:31640096:CT:C	donor_gain	1.0000
20:31640098:G:GG	donor_gain	1.0000
20:31643388:A:AG	acceptor_gain	1.0000
20:31643392:AACT:A	acceptor_gain	1.0000
20:31643395:T:A	acceptor_gain	1.0000
20:31643532:TACG:T	donor_loss	1.0000
20:31643536:G:GA	donor_loss	1.0000
20:31643537:T:A	donor_loss	1.0000
20:31644766:A:AG	acceptor_gain	1.0000
20:31644767:G:GT	acceptor_gain	1.0000
20:31644767:GTA:G	acceptor_gain	1.0000
20:31637963:G:GG	donor_gain	0.9900
20:31637963:GT:G	donor_loss	0.9900
20:31637967:G:GG	donor_gain	0.9900
20:31639932:GC:G	acceptor_gain	0.9900
20:31639932:GCC:G	acceptor_gain	0.9900
20:31640095:CCT:C	donor_gain	0.9900
20:31640100:A:AC	donor_loss	0.9900
20:31643389:C:G	acceptor_gain	0.9900

AlphaMissense

1119 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:31643418:T:C	F88L	0.989
20:31643420:C:A	F88L	0.989
20:31643420:C:G	F88L	0.989
20:31644895:G:C	W169C	0.974
20:31644895:G:T	W169C	0.974
20:31644825:G:C	R146P	0.972
20:31644874:G:C	W162C	0.972
20:31644874:G:T	W162C	0.972
20:31643497:G:A	G114E	0.970
20:31644893:T:A	W169R	0.967
20:31644893:T:C	W169R	0.967
20:31643410:G:C	R85P	0.960
20:31644872:T:A	W162R	0.960
20:31644872:T:C	W162R	0.960
20:31643496:G:A	G114R	0.958
20:31643496:G:C	G114R	0.958
20:31640066:G:C	W72C	0.957
20:31640066:G:T	W72C	0.957
20:31640054:G:C	E68D	0.955
20:31640054:G:T	E68D	0.955
20:31640064:T:A	W72R	0.955
20:31640064:T:C	W72R	0.955
20:31643430:T:C	F92L	0.951
20:31643432:T:A	F92L	0.951
20:31643432:T:G	F92L	0.951
20:31643520:T:A	W122R	0.951
20:31643520:T:C	W122R	0.951
20:31640086:A:T	E79V	0.949
20:31643475:G:C	G107R	0.945
20:31640045:G:C	K65N	0.943

dbSNP variants (sampled 300 via entrez): RS1000186674 (20:31642388 A>C,G), RS1000520734 (20:31643807 C>T), RS1000652549 (20:31636201 A>G), RS1001089730 (20:31637725 C>G), RS1002175038 (20:31645286 C>T), RS1002735916 (20:31638703 T>C,G), RS1003170910 (20:31637416 T>C), RS1004673135 (20:31643039 A>C), RS1004724836 (20:31637206 G>C), RS1004768046 (20:31636810 G>T), RS1006394011 (20:31638273 C>T), RS1006406122 (20:31637992 C>A), RS1006450338 (20:31638006 G>A,T), RS1006541943 (20:31639995 C>A,G,T), RS1006781093 (20:31639671 A>T)

Disease associations

OMIM: gene MIM:607976 | disease phenotypes: MIM:612714

GenCC curated gene-disease

Disease	Classification	Inheritance
pancreatic insufficiency-anemia-hyperostosis syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Limited	AR

Mondo (1): pancreatic insufficiency-anemia-hyperostosis syndrome (MONDO:0012992)

Orphanet (1): Pancreatic insufficiency-anemia-hyperostosis syndrome (Orphanet:199337)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000670	Carious teeth
HP:0000938	Osteopenia
HP:0000952	Jaundice
HP:0000988	Skin rash
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001738	Exocrine pancreatic insufficiency
HP:0001744	Splenomegaly
HP:0002099	Asthma
HP:0002240	Hepatomegaly
HP:0002570	Steatorrhea
HP:0002750	Delayed skeletal maturation
HP:0003193	Allergic rhinitis
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004395	Malnutrition
HP:0004490	Calvarial hyperostosis
HP:0010972	Anemia of inadequate production

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003030_10	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	3.000000e-06
GCST003030_9	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	4.000000e-06
GCST006979_537	Heel bone mineral density	4.000000e-13
GCST010703_295	Brain morphology (MOSTest)	1.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007679	oppositional defiant disorder measurement
EFO:0009270	heel bone mineral density
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567195	Exocrine Pancreatic Insufficiency, Dyserythropoietic Anemia, and Calvarial Hyperostosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
tebuconazole	decreases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Nickel	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.