C19orf22

R3HDM4
Identifiers
Aliases	R3HDM4, C19orf22, R3H domain containing 4
External IDs	MGI: 1924814; HomoloGene: 16343; GeneCards: R3HDM4; OMA:R3HDM4 - orthologs
Gene location (Human)
Chr.	Chromosome 19 (human)
End	913,245 bp
Gene location (Mouse)
Chr.	Chromosome 10 (mouse)
End	79,757,042 bp
RNA expression pattern
	Top expressed in
	blood; ; secondary oocyte; ; pancreatic ductal cell; ; granulocyte; ; beta cell; ; mucosa of ileum; ; mononuclear cell; ; monocyte; ; spleen; ; bone marrow;
	Top expressed in
	granulocyte; ; primary visual cortex; ; superior frontal gyrus; ; dentate gyrus of hippocampal formation granule cell; ; ascending aorta; ; aortic valve; ; muscle of thigh; ; lip; ; zygote; ; blood;
	More reference expression data
	n/a
Orthologs
	91300
	109284
	ENSG00000198858
	ENSMUSG00000035781
	Q96D70
	Q4VBF2
	NM_138774
	NM_177994; NM_001378997
	NP_620129
	NP_818775; NP_001365926
	Wikidata
View/Edit Human	View/Edit Mouse

Chromosome 19 open reading frame 22 (c19orf22) is a protein which in humans is encoded by the c19orf22 gene.^[5] The primary alias of the gene is R3H domain containing 4 (R3HDM4), but it is commonly referred to as c19orf22.

Gene

In the human genome, c19orf22 is located on the minus strand of chromosome 19, at 19p13.3.^[6] There are six exons in the sequence.

Location of c19orf22 on the chromosome.

Expression

The gene has the highest expression in bone marrow, followed by other tissues such as those found in the appendix and spleen.^[7] Similar results were found when cross checked across strict orthologs, including mouse and rat. Expression is ubiquitous and high across many tissues.

mRNA

The mRNA has 1803 base pairs.^[8] There are two known isoforms of c19orf22:

R3H domain-containing protein 4 isoform X1
R3H domain-containing protein 4 isoform X2

Conceptual translation

The depicted conceptual translation contains the 5'UTR region, protein sequence, and the end of the 3'UTR region.

Conceptual Translation Part 1 - 5'UTR region and protein sequence.

Conceptual Translation Part 2 - protein sequence.

Conceptual Translation Part 3 - protein sequence.

Conceptual Translation Part 4 - end of the 3'UTR region.

Homology/evolutionary history

There are many orthologs of c19orf22, both strict and distant, but there are no paralogs. C19orf22 is estimated to have first appeared in fish more than 550 million years ago.^[9] The gene is found in jawed and jawless fish. It is found in vertebrates, but it is not found in invertebrates. C19orf22 is evolving moderately slowly, as it is evolving more slowly than fibrinogen alpha and cytochrome C, which are indicators used to gauge evolution.

Strict and Distant Orthologs of c19orf22
	Genus and Species	Common Name	Taxonomic Group	Median Date of Divergence (MYA)	Accession Number	Sequence Length (aa)	Sequence Identity to Human (%)	Sequence Similarity to Human (%)
Mammals	Homo sapiens	Human	Primates	0	NP_620129.2	268	100	100
	Mus musculus	Mouse	Rodentia	87	NP_001365926.1	268	83.2	88.6
	Felis catus	Domestic Cat	Felis	94	XP_023098420.1	270	91.5	94.1
	Myotis daubentonii	Daubenton's Bat	Chiroptera	94	XP_059553395.1	272	88.2	91.2
	Trichechus manatus latirostris	Florida Manatee	Sirenia	99	XP_004378580.1	272	89.7	93.8
Reptiles	Crocodylus porosus	Saltwater Crocodile	Crocodilia	319	XP_019393792.1	261	67.7	78.1
	Python bivittatus	Burmese Python	Squamata	319	XP_007434704.1	274	60.4	72.9
	Pogona vitticeps	Bearded Dragon	Iguania	319	XP_020636752.1	286	57.6	67.8
	Chelonia mydas	Green Sea Turtle	Testudines	319	XP_037741422.1	281	57.2	68
Birds	Dromaius novaehollandiae	Emu	Casuariiformes	319	XP_025964072.1	273	64.5	76.4
	Scopus umbretta	Hamerkop	Peleconiformes	319	NXX59745.1	243	63.1	75.4
	Hirundo rustica	Barn Swallow	Passeriformes	319	NXW75483.1	243	63.1	74.6
	Meleagris gallopavo	Turkey	Galliformes	319	XP_010723277.1	282	60.1	71.5
Amphibians	Geotrypetes seraphini	West African Caecilian	Apoda	352	XP_033811581.1	258	61.9	77.6
Amphibians	Hyla sarda	Sardinian Tree Frog	Anura	352	XP_056373927.1	259	53	70.9
Fish	Salmo salar	Atlantic Salmon	Salmoniformes	429	ACI68345.1	253	46.6	60.1
	Solea solea	Flatfish	Pleuronectiformes	429	XP_058495099.1	256	50.7	65.4
	Scyliorhinus canicula	Small Spotted Cat Shark	Carcharhiniformes	462	XP_038632293.1	261	54.4	70.1
	Amblyraja radiata	Thorny Skate	Rajiformes	462	XP_032902988.1	260	52.4	68
	Petromyzon marinus	Sea Lamprey	Petromyzontiformes	563	XP_032809394.1	577	20.6	27.7

Protein

The protein contains 268 amino acids. C19orf22 has a molecular weight of 30.3 kDa.^[10] This is slightly below the average molecular weight of human proteins – ranging from 38kDa-46 kDa.

Protein interactions

Many proteins have been found to interact with c19orf22 using methods such as co-expression, experiments, databases, text mining, and protein neighborhood analysis. Descriptions of the most important ones are depicted in the table below.^[11]

Interacting Protein Network
Protein Name	Full Name	Description
MT-CO1	Mitochondrially Encoded Cytochrome C Oxidase 1	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-CO2	Mitochondrially Encoded Cytochrome C Oxidase 2	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
MT-CO3	Mitochondrially Encoded Cytochrome C Oxidase 3	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
CYC1	Cytochrome C1	Heme protein, mitochondrial, component of the ubiquinol-cytochrome c oxidoreductase, a multiunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.

Location and function

C19orf22 is consistently found in the nucleus and cytoplasm across orthologs.^[12] It is likely involved in enabling nucleic acid binding activity.

Post translational modifications

C19orf22 has multiple significant domains and regions throughout the protein sequence, including: a disordered region, a mixed charge region, a MVP (aka vault) region, and a R3H domain.^[13] Additionally, there are many phosphorylation sites throughout the sequence. While many are not included in the figure below, the two sites that are most significant are indicated by purple circles. The green region represents the vault region, and the yellow region represents the R3H domain. Disordered and mixed charged regions are also shown.

Significant regions found on c19orf22 protein sequence.

Protein structure

Tertiary structure of c19orf22 protein.

Secondary Structure

Alpha helices and beta sheets are evenly distributed throughout the protein sequence.^[14]

Tertiary structure

The tertiary structure of the c19orf22 protein is depicted.^[15] As per the key, spherical appearance indicates the most significant phosphorylation sites. Ball and stick appearance indicates the conserved arginine (R) rich regions in the sequence. Other domains and regions are labelled.

The tertiary structure contains positive, negative, neutral, and mixed charge regions.

Charge distribution of c19orf22 protein.

Clinical significance

Text based information

A connection has been found between issues with expression of c19orf22 and medical conditions such as arthritis and cancer.^[16]^[17] C19orf22 is identified as a gene that is a part of the erythropoietic signature. Genes in this signature are differentially expressed in sJIA and CAPS, and contain fold changes. C19orf22 is included in a list of genes that are depleted in patients with congenital heart defect. It may also be correlated with high myopia, learning difficulties, and dysmorphic figures that are symptoms of Peutz-Jeghers syndrome.

Common SNPs

There are multiple missense, 3'UTR, and intron variants in c19orf22.^[18] There is the lack of variations in the 5’UTR region due to its short length. Some variants are depicted in the table below.

Short Genetic Variations of c19orf22
SNP	Position	Transcript Change	Protein Change	Mutation Type	Variant Allele	Clinical Significance
rs1242243978	897,544	c.713G>A	Cys238Tyr	Missense variant	T	none
rs1248285503	897,551	c.706C>G	Pro236Ala	Missense variant	T	none
rs897751342	896,574	N/A	N/A	3’UTR variant	A and T	none
rs771454485	897,579 - 897,583	N/A	N/A	Intron variant	G and T	none
rs1408762003	894,877	N/A	N/A	2KB upstream variant	C	none
rs762093889	899,456	c.687G>A	Met229Ile	Missense variant	T	none
rs751997535	899,629	c.253G>A	Ala207Thr	Missense variant	T	none

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000198858 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000035781 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "R3H domain-containing protein 4 [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-10-15.
^ "Human BLAT Search". genome.ucsc.edu. Retrieved 2023-10-15.
^ "R3HDM4 R3H domain containing 4 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-10-15.
^ "NCBI Nucleotide". 25 December 2022.
^ "BLAST".
^ "Statistical Analysis of Proteins".
^ "Stringdb".
^ "Human Protein Atlas".
^ "ScanProsite".
^ "Chou and Fasman Secondary Structure Prediction Server".
^ "iCN3D".
^ Nirmala N, Grom A, Gram H (September 2014). "Biomarkers in systemic juvenile idiopathic arthritis: a comparison with biomarkers in cryopyrin-associated periodic syndromes". Current Opinion in Rheumatology. 26 (5): 543–552. doi:10.1097/BOR.0000000000000098. PMC 4487522. PMID 25050926.
^ Qureshi MA, Khan S, Tauheed MS, Syed SA, Ujjan ID, Lail A, Sharafat S (November 2020). "Pan-Cancer Multiomics Analysis of TC2N Gene Suggests its Important Role(s) in Tumourigenesis of Many Cancers". Asian Pacific Journal of Cancer Prevention. 21 (11): 3199–3209. doi:10.31557/APJCP.2020.21.11.3199. PMC 8033114. PMID 33247676.
^ "NCBI dbSNP".