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C10ORF25 (Chromosome 10 open reading frame 25)

Chromosome 10 open reading frame 25 (c10orf25) is a protein which in humans is encoded by C10orf25 gene.

Gene

Figure 1: Image of Chromosome 10 showing the location of C10orf25. The red line indicates the exact location of the gene, seen on the long arm of the chromosome.

C10orf25 is 668 base pairs long and it encodes a protein that is 122 amino acids long.The gene is found on the long arm of chromosome 10, and its specific location is 10q11.21.

The C10orf25 gene contains about 12 different gt-at intron regions. The gene is unique in having 5 alternatively spliced variants and 3 unspliced forms. The gene also consists of 3 non-overlapping alternative last exons and 3 alternative promoters. There are also 7 validated alternative polyadenylation sites throughout the gene. The protein coding sequence consists of 6 exon sequences.

RNA

The alias of C10orf25 is known as ZNF22-AS1 which is 8,972 base pairs long. The mRNA transcript is 668 base pairs long to encode a protein that is 122 amino acids long.

Figure 3: Conceptual Translation of human C10orf25 with labeled domains, motifs, post-translational modifications and conserved amino acids are recognized in bold.

Figure 2: Schematic of C10orf25 and its promoter sequence. The dark green region represents the promoter region. The dark brown regions are the 5’ UTR and 3’UTR regions, whereas the light brown regions are the exons. The black lines represent the introns. The arrow represents the transcriptional start site.

Expression

Gene C10orf25 has been found to be highly expressed in the appendix, fat cells and is moderately expressed in the kidney, thyroid, and nervous system tissues ike the brain and cerebellum. The gene has also shown significant prevalence in expression in the testis, lungs, and liver. Small significances in expression have also been discovered in adipose tissue, ovary, the placenta, hypothalamus, and spleen.

Protein

The encoded protein C10orf25 weighs 14.4kDa. The isoelectric point of the protein is predicted to be 10.26. The protein is composed of mostly proline which is a neutral amino acid. The next most common amino acids serine, arginine, and leucine. Serine is a neutral amino acid, arginine is positively charged, and leucine is nonpolar. According to the KR-ED analysis, the protein is more positively charged.

Cellular Localization

This protein is predicted to be located in the extracellular region. DeepLoc predicts C10orf25 to be localized in the mitochondria and membrane. The top localization likelihood scores in cell were for the mitochondrion at 0.4413 and the nucleus score at 0.1209. Data from PSORT II shows the protein is localized in the membrane, so it is highly possible it is also localized in the membrane and has a function there. C10orf25 is a secretory protein in the mitochondria and the membrane.

Domains and Motifs

The C-terminus is located on the inside of the protein.

Figure 4: Human C10orf25 protein is depicted in light blue, the mitochondrial localization sequence is highlighted in red, the cleavage signal peptide is highlighted in yellow, the conserved phosphorylation sites are denoted by yellow circles, the conserved O-glycosylation sites are denoted by green squares, and the conserved N-glycosylation sites are denoted by pink rectangles. Made by IBS Cuckoo.

Post-Translational Modifications

The cleavage signal peptide is between amino acids 1-28 and the cleavage peptide is between amino acids 28 and 29.

NetPhos predicts C10orf25 undergoes phosphorylation post-translation at 21 different sites on the protein by 9 different kinases and 9 sites by unspecified kinases. The amino acid with the highest level of phosphorylation is serine. The bars that go over the line of threshold is due to multiple kinases that target the same serine, threonine, or tyrosine.

Structure

The protein composed of 5 beta sheets and 6 alpha helices. AlphaFold predicts the structure of C10orf25 to be of low to medium confidence. The protein structure is also highly conserved.

Figure 5: 3D predicted structure fold of C10orf25 from AlphaFold

Orthologs

Orthologs for protein C10orf25 are found in mammals only, mostly in primates and marine mammals. There were no orthologs present in Marsupials, Monotremes, Birds, Reptilia, Amphibia, Fish, or Plants. Down below is the ortholog chart that shows the gives the genus and species, the common name, taxon, percent similarity, and percent identity.

C10orf25	Genus and Species	Common Name	Taxon	Similarity (%)	Identity (%)	Accesion #
Mammalia	Homo Sapiens	Human	primates	100	100
Mammalia	Pan troglodytes	Chimpanzee	primates	97.5	97.54	XP_016773654.1
Mammalia	Pongo abelii	Sumatran orangutan	primates	62.1	60.4	XP_024109826.1
Mammalia	Nomascus leucogenys	Northern white-cheeked gibbon	primates	82.9	81.4	XP_030655093.1
Mammalia	Colobus angolensis palliatus	Angola colobus	primates	87.2	83.25	XP_0118909174.1
Mammalia	Macaca mulatta	Indochinese rhesus macaque	primates	84	80.8	XP_015002402.1
Mammalia	Macaca nemestrina	Southern pig-tailed macaque	primates	83.2	80	XP_024650102.1
Mammalia	Pilicolobus tephrosceles	Ugandan red colobus	primates	88.9	84.92	XP_023054351.3
Mammalia	Mandrillus leucophaeus	Drill	primates	87.9	86.29	XP_011833969.1
Mammalia	Theropithecus gelada	Gelada	primates	82.4	80	XP_025253169.1
Mammalia	Aotus nancymaae	Nancy Ma's night monkey	primates	74	70.08	XP_021527937.1
Mammalia	Microcebus murinus	Gray mouse lemur	primates	49.6	47.37	XP_020136089.1
Mammalia	Propithecus coquereli	Coquerel's sifaka	primates	47.2	40.7	XP_012509356.1
Mammalia	Balaenoptera acutorostrata scammoni	Minke whale	Artiodactyla	23.9	56.9	XP_028020796.1
Mammalia	Balaenoptera acutorostrata scammoni	Minke whale	Cetacea	23.9	56.9	XP_028020796.1

Figure 7: Phylogeny tree showing the lines of evolutionary descent of C10orf25 made using Phylogeny.

Figure 6: Date of Divergence of C10orf25 compared to the evolutionary rate of Cytochrome C and Fibrinogen Alpha Chain.

The C10orf25 protein is estimated to have first appeared in Minke Whales 94 million years ago. This was the only marine mammal the protein was found in. The gene only appears vertebrates and evolved from Minke Whales to primates. The gene family for C10orf25 is relatively small and is a moderately early diverging lineage.

There are no paralogs for C10orf25.

C10orf25 is evolving moderately slowly compared to reference sequences cytochrome C and fibrinogen alpha chain.The percent similarity and identity for cytochrome C sequence and Fibrinogen Alpha Chain sequence were calculated in EMBOSS Needle against the sequences for C10orf25. Overall, this graph shows the mutation rate of C10orf25 in comparison to mutation rates of cytochrome c and fibrinogen alpha chain. From the graph below we can see that C10orf25 is evolving relatively quickly compared to fibrinogen and cytochrome C.

Function

The C10orf25 protein plays a role in gene regulation and expression in the nuclei and is secreted in the mitochondria.

Interacting proteins

The C10orf25 protein interacts with two histone proteins: HIST1H1C and HIST3H3. HIST3H3 is is a core component of nucleosomes. HIST1H1C is a histone H1 protein that binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. It also interacts with a Wnt Ligand Secretion Mediator protein, WLS ^[6]. WLS plays a key role in the regulation of subcellular location, expression, binding and organelle-specific association of Wnt proteins. It regulates Wnt protein sorting and secretions in a regulatory feedback mechanism. WLS is associated with diseases like Zaki Syndrome and Volkmann Contracture.

C10orf25 protein also interacts with COG1212 between amino acids 71-115 , which is the only protein that is a part of protein superfamily cl42799, in Conserved Protein Domain Family KdsB. COG1212 is an acid synthetase/

Clinical Significance

The C10orf25 gene has been tested and confirmed associated with Alzheimer’s Disease.⁴ A study performed a chromosome-10 specific association study to Alzheimer’s including 1,412 SNPs to identify genes that leave people susceptible for late-onset Alzheimer disease. C10orf25 showed a hit for the sample done in the UK. The marker found for the gene is rs2297492.

Another study discovered that C10orf25 in a GWAS study evaluating unique and shared genes associated with cognitive deficits had a p-value score of 0.00017. The gene only showed one domain in the GWAS. The polygenic risk score analyses of the GWAS hits showed a significant negative correlation for verbal learning and memory, which is what gene C10orf25 is associated with. The study was able to conclude that negative cognitive domain scores are associated to a higher schizophrenia genetic risk.

A study, Lysine-specific demethylase 1 depletion effect on neuroblastoma cell line experimented on the effect of lysine demethylase 1 depletion on a neuroblastoma cell line The study found that when the cell line was depleted of LSD1, expression of C10orf25 was higher than the control cell line that was not depleted of LSD1.

The study, tested the effect of sodium butyrate, chemotherapy, and a combination of the two on Raji Burkitt’s lymphoma cells. The expression of C10orf25 in R.B. lymphoma cells was much higher than the control when being treated with sodium butyrate. When treated with only chemotherapy, the expression of C10orf25 was less than when only treated with sodim butyrate. When the R.B. lymphoma cell line was treated with both sodium butyrate and chemotherapy, the expression of C10orf25 was much higher than the latter results.

The study, Antiretroviral therapy effect on brain of patients with HIV-associated neurocognitive disorders evaluated the effect of antiretroviral therapy on patients with HIV-associated neurocognitive disorders. The results determined both overexpression and underexpression of C10orf25 in these cells in both the uninfected control and effected, in which both had groups that received the therapy and another that was untreated. There was more underexpression of C10orf25 in the group with the HIV disease that received the antiretroviral therapy, this indicates the possible correlation of C10orf25 playing a role in HIV-associated neurocognitive disorders.