Chromosome 19 open reading frame 22 (c19orf22) is a protein which in humans is encoded by the c19orf22 gene. 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. There are six exons in the sequence.
Expression The gene has the highest expression in bone marrow, followed by other tissues such as those found in the appendix and spleen. 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. 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.
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. 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 SpeciesCommon NameTaxonomic GroupMedian Date of Divergence (MYA)Accession NumberSequence Length (aa)Sequence Identity to Human (%)Sequence Similarity to Human (%)MammalsHomo sapiensHumanPrimates0NP_620129.2268100100Mus musculusMouseRodentia87NP_001365926.126883.288.6Felis catusDomestic CatFelis94XP_023098420.127091.594.1Myotis daubentoniiDaubenton's BatChiroptera94XP_059553395.127288.291.2Trichechus manatus latirostrisFlorida ManateeSirenia99XP_004378580.127289.793.8ReptilesCrocodylus porosusSaltwater CrocodileCrocodilia319XP_019393792.126167.778.1Python bivittatusBurmese PythonSquamata319XP_007434704.127460.472.9Pogona vitticepsBearded DragonIguania319XP_020636752.128657.667.8Chelonia mydasGreen Sea TurtleTestudines319XP_037741422.128157.268BirdsDromaius novaehollandiaeEmuCasuariiformes319XP_025964072.127364.576.4Scopus umbrettaHamerkopPeleconiformes319NXX59745.124363.175.4Hirundo rusticaBarn SwallowPasseriformes319NXW75483.124363.174.6Meleagris gallopavoTurkeyGalliformes319XP_010723277.128260.171.5AmphibiansGeotrypetes seraphiniWest African CaecilianApoda352XP_033811581.125861.977.6Hyla sardaSardinian Tree FrogAnura352XP_056373927.12595370.9FishSalmo salarAtlantic SalmonSalmoniformes429ACI68345.125346.660.1Solea soleaFlatfishPleuronectiformes429XP_058495099.125650.765.4Scyliorhinus caniculaSmall Spotted Cat SharkCarcharhiniformes462XP_038632293.126154.470.1Amblyraja radiataThorny SkateRajiformes462XP_032902988.126052.468Petromyzon marinusSea LampreyPetromyzontiformes563XP_032809394.157720.627.7
Protein The protein contains 268 amino acids. C19orf22 has a molecular weight of 30.3 kDa. 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. +Interacting Protein NetworkProtein Name Full Name Description MT-CO1Mitochondrially 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-CO2Mitochondrially 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-CO3Mitochondrially Encoded Cytochrome C Oxidase 3 Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.CYC1Cytochrome 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. 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 (a.k.a. vault) region, and a R3H domain. 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.
Protein structure
Secondary Structure Alpha helices and beta sheets are evenly distributed throughout the protein sequence.
Tertiary structure The tertiary structure of the c19orf22 protein is depicted. 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.
Clinical significance
Text based information A connection has been found between issues with expression of c19orf22 and medical conditions such as arthritis and cancer. 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. 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 c19orf22SNP 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
Further reading Journal articles that can provide more insight: The DNA sequence and biology of human chromosome 19 Integrating RNA-Seq With GWAS Reveals a Novel SNP in Immune-Related HLA-DQB1 Gene Associated With Occupational Pulmonary Fibrosis Risk: A Multi-Stage Study Phosphorylation Drives a Dynamic Switch in Serine/Arginine-Rich Proteins