Chromosome 3 open reading frame 5 (C3orf52), also known as TTMP or TPA-Induced Transmembrane Protein (accession: NP_078892), is an uncharacterized protein encoded in humans by the C3orf52 gene. C3orf52 is located on the plus strand of chromosome 3, at gene locus q.13.2. C3orf52 encodes a transmembrane protein which is believed to be responsible for regulating some aspect of epithelial tissue and evidence supports a theory of C3orf52 acting in some capacity to impact hair loss in humans due to interactions with lysophosphatidic acid production required for hair follicle formation.
Expression patterns
Analysis of C3orf52 samples throughout the human body has indicated that the protein displays approximately fourfold variation throughout the body and that C3orf52 is tissue-restricted and highly regulated in its expressions. The highest concentration of the protein is found in the thyroid and salivary glands, while there have been moderate concentrations reported in the skin, pancreas, and stomach.
Immunohistochemical micrographs from The Human Protein Atlas show that C3orf52 is expressed in colon and stomach tissues, with concentrations of the protein found along the luminal borders of the epithelial cells in the colon. This suggests that C3orf52 expression is membrane-associated in nature.
Molecular features
mRNA C3orf52 has two transcript variants. Transcript variant 1 is a shorter transcript (753 nucleotides) but encodes a longer isoform (TPA-induced transmembrane protein isoform 1). Transcript variant 2 (654 nucleotides) encodes a shorter isoform (TPA- induced transmembrane protein isoform 2) with a different C-terminus. Transcript variant 2 consists of six exons.
Protein C3orf52 consists of a disordered region, a transmembrane region, and a major polyA site. The molecular weight is of 24.3 kDa. This protein is predicted to be localized primarily in the cytoplasm (94.1%), with specific localization to the endoplasmic reticulum (44.4%).
The protein is associated with two distinct isoforms; isoform 1 is 250 amino acids long, while isoform 2 is 217 amino acids long. In human research, isoform 2 is the predominant variation found and is the most common focus for research on C3orf52.
Compositional analysis has indicated that this protein is acidic in nature, with a predicted isoelectric point of 3.99. Additionally, results show a high-scoring transmembrane segment spanning amino acids 66 to 93, which is also among the protein's most hydrophobic segment. C3orf52 contains a repetitive four-amino acid motif, including a sequence reading "LELS" at amino acids 13-16 and repeating at positions 101–104, this region is not conserved among orthologs.
Post-translational modifications Human C3orf52 is predicted to contain three phosphorylation sites at positions 140,180, and 183, two N-glycosylation sites at positions 106 and 159, and three O-linked glycosylation sites at positions 7, 26, and 37. All of the O-linked glycosylation sites are within the disordered region of this protein. This indicates that C3orf52 is a moderately regulated protein that likely functions more as a scaffold than as a structural protein.
Evolutionary history
Paralogs An NCBI protein BLAST search showed no known paralogs of C3orf52 in humans.
Orthologs C3orf52 retains its sequence with identifiable orthologs exclusively within vertebrates (see Table 1 below), specifically up to the elasmobranchii lineage, but is absent in more distantly related groups. Outside of vertebrates, including all invertebrate animals, bacteria, archaea, fungi, plants, and protists, no identifiable sequence homology is detected for this protein. The most distant homolog detected of C3orf52 was in the elephant shark (Callorhinchus milli), which diverged about 495.2 million years before humans, suggesting that this is approximately when the C3orf52 gene first arose.
+Table 1. Human C3orf52 orthologs sorted by estimated date of divergence from humans and protein sequence identityGenus and speciesCommon nameTaxonomic groupDate of divergence (MYA)Sequence length (AA)AA identity (%)AA similarity (%)Accession numberHomo sapiensHumanPrimates0217100100NP_078892.3Pan troglodytesChimpanzeePrimates6.42179798XP_001154447.2Trachypithecus francoisiFrancois' leaf monkeyPrimates28.82178993XP_033067213.1Equus przewalskiiPrzewalski's horsePerissodactyla942507787XP_008528528.1Diceros bicornis minorSouth-central black rhinocerosPerissodactyla942517485XP_058411758.1Tachyglossus aculeatusAustralian echidnaMonotremata1802145267XP_038622330.1Struthio camelusCommon ostrichStruthioniformes3192183754XP_068764855.1Empidonax trailliiWillow flycatcherPasseriformes3192113653XP_027757055.1Mauremys reevesiiChinese pond turtleTestudines3192334358XP_039395838.1Carettochelys insculptaPig-nosed turtleTestudines3192144156XP_074839613.1Chelonoidis abingdoniiPinta island tortoiseTestudines3192184054XP_074928790.1Ambystoma mexicanumAxolotlCaudata3522394256XP_069492559.1Rhinatrema bivittatumRhinatremaGymnophiona3522174160XP_029434280.1Pleurodeles waltlIberian ribbed newtCaudata3522364052XP_069060250.1Microcaecilia unicolorTiny cayenne caecilianGymnophiona3522253958XP_030060067.1Siphateles boraxobiusBorax lake chubCypriniformes4292483452XP_077063864.1Acipenser ruthenusSterletAcipenseriformes4292603352XP_058884635.1Etheostoma spectabileOrangethroat darterPerciformes4292683249XP_032360225.1Pseudorasbora parvaStone morokoCypriniformes4292513049XP_067307703.1Carcharodon carchariasGreat white sharkLamnifores4623762950XP_041067311.1Callorhinchus milliElephant sharkChimaeriformes4958351840XP_007894202.1
Protein divergence C3orf52 is evolving more quickly than other common proteins including cytochrome c and fibrinogen alpha chain. This would suggest some sort of selective pressure on the protein driving its rapid evolution.
Protein interactions ProteinIDDescriptionDetection methodSubcellular locationHypotrichosis 7HYPT7Mutations in the lipase H gene are linked to autosomal recessive hypotrichosis affinity chromatography technology Endoplasmic reticulum and luminal side of membranes Chromosome 19 open reading frame 75C19orf75Uncharacterized protein affinity chromatography technology Predicted membrane-associatedNeonatal fragment crystallizable receptor FCRNNeonatal Fc receptor. Responsible for transferring immunity from mother to newbornaffinity chromatography technology Endosomal membrane, plasma membrane, and endoplasmic reticulumTransmembrane protein 30BTMEM30BSubunit of P4-ATPase complex which is involved in the transport of lipids across the cell membraneaffinity chromatography technology Endoplasmic reticulum and plasma membraneB-cell antigen receptor complex-associated protein beta chain CD79bForms the B-cell receptors and is required to initiate signal cascade when antigen binds to B-cellaffinity chromatography technology Plasma membranePlatelet glycoprotein 4CD36Multifunctional glycoprotein that acts as a receptor for molecules such as fatty acids, collagen, and thrombospondin affinity chromatography technology Plasma membrane and endosome Table 2. Protein interactions found using BioGrid. All interactions were physical interactions and had very confident significant scores.
A STRING protein association search yielded no confident results, or ones that seem significant based on previous findings.
Conceptual translation
Conceptual translation of the human C3orf52 protein isoform 2, along with full mRNA and annotations is shown in Figure 4.
Clinical significance Several studies resulting in an initial information search on C3orf52 focused on the likely involvement of this gene in lipase H-mediated lysophosphatidic acid biosynthesis, a step in hair-follicle formation. Evidence shows that decreased expression of C3orf52 has been linked to localized autosomal recessive hypotrichosis, a condition resulting in the absence of hair. There were three relevant single-nucleotide polymorphisms found with clinical significance linked to hypotrichosis 15 (rs764787339, rs2472299130, rs545208237) (Table 2).
Apart from articles on the involvement of C3orf52 in hair loss, PubMed and Google Scholar provided a couple of other potential linkages between this gene and diseases, specifically a variety of cancers. One of the more eye-catching articles found associations of this gene in the development of multifocal and multicentric breast cancer, and is looking into it as a current marker for distinguishing multifocal and multicentric breast cancer from unifocal breast cancers.
Another study proposes looking at C3orf52 as a potential marker as a prognosis gene of cancer in a study looking at DNA copy number variations, which are common in cancer cells. Additionally, C3orf52 is linked to be downregulated in clear-cell renal cell carcinoma, and its reduced expression was linked to later disease stage and poorer overall survival of clear-cell renal cell carcinoma patients.
Single nucleotide polymorphisms SNPPositionBase change AA change Mutation typeSignificanceClinical significance rs764787339bp 34
AAG to A
G to C
G to TGlu12Lys
Glu12Gln
Glu12TerMissense variant
Missense variant
Stop gained Within the disordered region; also within the very beginning of the coding sequence Hypotrichosis 15 rs2472299130bp 438 - 442
AA 148 N/AThr148fs
(frameshift variant) Deletion Directly following a string of highly conserved AAHypotrichosis 15 rs545208237bp 492 T to A
T to CTyr164Ter
Tyr164=Stop gained
Synonymous variant On a conserved AAHypotrichosis 15 rs16859190bp 331
AA 111A to GI to VMissense variant On a non-conserved AA within a string of conserved AANoners340167bp 430
AA 144G to A
G to CG to R
G to CMissense variants Within SEA domain Noners16859172bp 197
AA 66T to CL to PMissense variant On a conserved AA, within transmembrane regionNoners111954756bp 566
AA 189 G to CG to AMissense variant On a non-conserved AA within a string of conserved AANone Table 3. Summary of common single-nucleotide polymorphism mutations within human C3orf52 including their position of occurrence and significance. Single nucleotide polymorphisms were found using variation viewer.
SNPTraitLocationrs12053863-?Glucose metabolism
Hearing impairment3:112100677rs79754744-GEosinophil count 3:112111457rs76093951-TBilirubin measurement3:112117176rs7649379-?Eosinophil count 3:112121666rs1492488-CEosinophil percentage of leukocytes3:112122499 Table 4. Summary of GWAS catalog results. Majority of the results show immunity association within single nucleotide polymorphisms, particularly eosinophil count.
References
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