TMEM248

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Transmembrane protein 248, also known as C7orf42, is a gene that in humans encodes the TMEM248 protein. This gene contains multiple transmembrane domains and is composed of seven exons.TMEM248 is predicted to be a component of the plasma membrane and be involved in vesicular trafficking.[1][2] It has low tissue specificity, meaning it is ubiquitously expressed in tissues throughout the human body. Orthology analyses determined that TMEM248 is highly conserved, having homology with vertebrates and invertebrates. TMEM248 may play a role in cancer development. It was shown to be more highly expressed in cases of colon, breast, lung, ovarian, brain, and renal cancers.[3]

TMEM248
Identifiers
AliasesTMEM248, C7orf42, transmembrane protein 248
External IDsMGI: 1918917 HomoloGene: 9951 GeneCards: TMEM248
Orthologs
SpeciesHumanMouse
Entrez

55069

71667

Ensembl

ENSG00000106609

ENSMUSG00000053094

UniProt

Q9NWD8

Q3TBN1

RefSeq (mRNA)

NM_017994

NM_001081394
NM_027854

RefSeq (protein)

NP_060464

NP_001074863
NP_082130

Location (UCSC)Chr 7: 66.92 – 66.96 MbChr 5: 130.25 – 130.27 Mb
PubMed search[6][7]
Wikidata
View/Edit HumanView/Edit Mouse

Gene[edit]

TMEM248 is located at chromosome 7 at location 7q11.21 with 37,327 base pairs, spanning from position 66,921,225 to 66,958,551.[8][9] It has 7 exons and is located on the sense strand.[9][10]

Transcript[edit]

Figure 1. Bird's eye view of TMEM248 promoter region and gene.

TMEM248 contains 7 exons, seen in Figure 1. A single gene can have multiple isoforms produced by alternative splicing. TMEM248 has four isoforms summarized in Table 1.

Table 1. Isoforms of Homo Sapiens TMEM248 produced by alternative splicing.
Isoform Number Accession Number Transcript Length Protein Length Molecular Weight
1 Q9NWD8-1,[11] NM_017994.5[12] 4,229 314 35 kDa
X1 XP_024302587.1[13] 4,246 322 36 kDa
X2 XM_024446821.2[14] 4,008 314 35 kDa
X3 XM_024446820.2[15] 4,010 314 35 kDa

Messenger RNA[edit]

Figure 2. Annotated conceptual translation of human TMEM248

An annotated conceptual translation of TMEM248 is seen in Figure 1. TMEM248 mRNA is most highly expressed in the thyroid, endometrium, prostate, testis, and ovaries, though it is ubiquitously expressed at varying levels in most tissue types.[9]

Protein[edit]

TMEM248 is a multi-pass component of the membrane and functions in protein binding and vesicular transport.[1][2] TMEM248 has both low tissue and single cell type specificity, but single cell expression cluster is in macrophages.[16] The polypeptide chain of TMEM248 is 314 amino acids long and the molecular weight is approximately 35 kDa. TMEM248 is threonine-rich, meaning that it has a higher-than-average amount of threonine residues.[17] Additionally, it is a more acidic than basic molecule.[17] The basal isoelectric point of TMEM248 is 5.91 pH.

Subcellular localization[edit]

Immunofluorescence staining shows TMEM248 localization to vesicles.The subcellular location of TMEM248 is predicted to be the endoplasmic reticulum membrane, in vesicles, and in the plasma membrane.[18][19]

Post-translational modifications[edit]

Predicted post-translational modifications for TMEM248 protein include glycosylation, ubiquitylation, and phosphorylation. Ubiquitylation at K228, K240, and K245, glycosylation at N80, and phosphorylation at Y13 and S300 were experimentally determined.[10][20]

Figure 3. TMEM248 domain and post translational modification diagram. P represents phosphorylation sites, Ub represents ubiquitylation sites, and G represents glycosylation sites. TMEM (#) represents predicted transmembrane domains[21]

Homology and evolution[edit]

Homologs of the TMEM248 gene are found in vertebrates and invertebrates. The most distant orthologs of TMEM248 are in echinoderms, mollusks, and arthropods, which diverged approximately 680 million years ago.[22] Orthologs of TMEM248 are not found in annelids, nematodes, cnidarians, sponges, fungi, plants, or bacteria.

Table 2. Summary of selection of TMEM248 orthologs.[23]
Genus and Species Common name Order DoD* (MYA) Accession Length % Similarity % Identity
Homo sapiens Human Primate 0 NP_060464.1 314 100 100
Mus musculus House mouse Rodentia 87 NP_082130.1 314 98.7 94.6
Phyllostomus discolor Pale spear-nosed bat Chiroptera 94 XP_028369740 314 99.4 96.5
Gallus gallus Chicken Galiformes 319 XP_024997905.1 324 95.2 90.4
Hirundo rustica Barn swallow Passeriformes 319 XP_039938558 314 95.9 91.1
Mauremys mutica Yellow pond turtle Testudines 319 XP_044849258 314 96.2 92.0
Bufo bufo Common toad Anura 353 XP_040279401 315 94.3 85.1
Xenopus tropicalis Western clawed frog Anura 353 NP_001007494.1 315 93.7 84.1
Geotrypetes seraphini Gaboon caecilian Gymnophiona 353 XP_033777821 313 93.9 88.5
Ictalurus punctatus Channel catfish Siluriformes 431 XP_017315532 315 92.1 81.0
Danio rerio Zebrafish (teleost) Cypriniformes 431 NP_001013548 314 88.0 76.5
Triplophysa tibetana Stone loach (ray finned fish) Cypriniformes 431 KAA0716418 332 88.0 78.0
Chiloscyllium plagiosum White spotted bamboo shark Orectolobiformes (carpet) 464 XP_043574478 321 92.5 83.8
Carcharodon carcharias Great white shark Lamniformes (mackerel) 464 XP_041053841 321 92.2 83.8
Strongylocentrotus purpuratus Pacific purple sea urchin Echinoida 619 XP_003725226.2 307 50.9 34.0
Apostichopus japonicus Sea cucumber Stichopodidae 619 PIK58986.1 244 37.0 19.1
Aplysia californica California sea hare Anaspidea 680 XP_005091558.1 372 43.6 27.9
Blattella germanica German cockroach Blattodea 680 PSN49789.1 275 48.4 30.8
Cryptotermes secundus Drywood termite Isoptera 680 XP_023712247.1 281 45.9 29.8
Parasteatoda tepidariorum Common house spider Araneae 680 XP_042905814.1 305 43.7 23.6
Mizuhopecten yessoensis Yesso scallop Pectinida 680 OWF52152 367 46.2 30.1
Plakobranchus ocellatus Ring sap sucking slug Saccoglossa 680 GFO37695.1 406 40.1 26.5

*DoD = date of divergence; MYA = million years ago.

Figure 4. TMEM248 evolution and corrected sequence divergence compared to fibrinogen a-chain evolution (red) and cyt c evolution (yellow).

TMEM248 has two paralogs in humans: TMEM219 and insulin-like growth factor binding protein 3 (IGFBP3) receptor isoform 2 precursor. The TMEM219 protein has 34.9% similarity and 21.1% identity to TMEM248. The IGFBP3 receptor isoform 2 precursor protein has 36.4% similarity and 21.9% identity to TMEM248.

TMEM219 is a death receptor that induces apoptosis (a type of programmed cell death) via a caspase-8 dependent mechanism, and the ligand for this receptor is IGFBP3. The TMEM219/IGFBP3 signaling pathway is experimentally shown to regulate pancreatic beta cell function.[24]

Table 3. Selection of Homo sapiens TMEM248 paralogs and their orthologs in other species.
Genus and Species Common name Order DoD (MYA) Accession Length % Similarity % Identity
Homo sapiens TMEM219 Human Primate 0 KAI2578024.1 213 34.9 21.1
Homo sapiens IGFBP3 Human Primate 0 P_001356618.1 240 36.4 21.9
Mus musculus TMEM219 House mouse Rodentia 87 AAH46763.1 240 34.9 21.1
Mus musculus IGFBP3 House mouse Rodentia 87 NP_081103.1 240 36.8 21.4
Python bivittatus IGFBP3 Burmese python Squamata 319 XP_007424393 242 40.5 21.8
Geotrypetes seraphini IGFBP3 Gaboon caecilian Gymnophiona 353 XP_033802587 373 32.6 19.7
Denticeps clupeoides IGFBP3 Denticle herring Clupeiformes 431 XP_028848129 300 40.7 19.8

Clinical significance[edit]

TMEM248 has proposed connections to various forms of cancer. Mutations in the gene have been recorded in tumor samples from stomach, colorectal, lung, bladder, ovarian, endometrial, and breast cancer.[16] Of the tumor samples observed, stomach tumors were most likely to contain mutations of TMEM248. There is relatively higher expression of TMEM248 in colon, breast, lung, ovarian, brain, and renal cancer.[25] Multiple myeloma (cancer of unrestricted B cell proliferation in bone marrow) progression and drug sensitivity could regulate TMEM248 expression.[26] These experimentally determined conclusions implicate TMEM248 playing a role in cell proliferation, and make expression of TMEM248 a potential candidate for more intensive studies in the development of cancer in these organs. However, the TMEM248 gene product is not prognostic for cancer with the current available research.

References[edit]

  1. ^ a b "TMEM248 transmembrane protein 248 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-20.
  2. ^ a b "TMEM248 Polyclonal Antibody (PA5-53435)". www.thermofisher.com. Retrieved 2022-12-15.
  3. ^ Sehovic, Emir; Hadrovic, Adem; Dogan, Senol (2019-11-10). "Detection and analysis of stable and flexible genes towards a genome signature framework in cancer". Bioinformation. 15 (10): 772–779. doi:10.6026/97320630015772. ISSN 0973-2063. PMC 6900328. PMID 31831960.
  4. ^ a b c GRCh38: Ensembl release 89: ENSG00000106609 – Ensembl, May 2017
  5. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000053094 – Ensembl, May 2017
  6. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  7. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  8. ^ "TMEM248". UCSC Genome Browser. University of California, Santa Cruz. Retrieved 3 August 2022.
  9. ^ a b c "TMEM248 transmembrane protein 248 [ Homo sapiens (human) ]". National Library of Medicine. NCBI. Retrieved 30 July 2022.
  10. ^ a b "TMEM248 Gene - Transmembrane Protein 248". GeneCards. Weizmann Institute of Science. Retrieved 3 August 2022.
  11. ^ "UniProt". www.uniprot.org. Retrieved 2022-12-15.
  12. ^ "Homo sapiens transmembrane protein 248 (TMEM248), mRNA". 2021-06-26. {{cite journal}}: Cite journal requires |journal= (help)
  13. ^ "transmembrane protein 248 isoform X1 [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-15.
  14. ^ "PREDICTED: Homo sapiens transmembrane protein 248 (TMEM248), transcript variant X2, mRNA". 2022-04-05. {{cite journal}}: Cite journal requires |journal= (help)
  15. ^ "PREDICTED: Homo sapiens transmembrane protein 248 (TMEM248), transcript variant X3, mRNA". 2022-04-05. {{cite journal}}: Cite journal requires |journal= (help)
  16. ^ a b "Tissue expression of TMEM248 - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2022-12-15.
  17. ^ a b "EBI Tools: Job not available". www.ebi.ac.uk. Retrieved 2022-12-15.
  18. ^ "PSORT WWW Server". psort.hgc.jp. Retrieved 2022-12-15.
  19. ^ "{{ngMeta['og:title']}}". bio.tools. Retrieved 2022-12-15.
  20. ^ "TMEM248 (human)". www.phosphosite.org. Retrieved 2022-12-15.
  21. ^ "IBS - Online". ibs.biocuckoo.org. Retrieved 2022-12-15.
  22. ^ "TimeTree of Life". TimeTree 5, The TimeScale of Life. Institute for Genomics and Evolutionary Medicine Center of Biodiversity Temple University. Retrieved 3 August 2022.
  23. ^ "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2022-12-15.
  24. ^ D’Addio, Francesca; Maestroni, Anna; Assi, Emma; Ben Nasr, Moufida; Amabile, Giovanni; Usuelli, Vera; Loretelli, Cristian; Bertuzzi, Federico; Antonioli, Barbara; Cardarelli, Francesco; El Essawy, Basset; Solini, Anna; Gerling, Ivan C.; Bianchi, Cristina; Becchi, Gabriella (2022-02-03). "The IGFBP3/TMEM219 pathway regulates beta cell homeostasis". Nature Communications. 13 (1): 684. Bibcode:2022NatCo..13..684D. doi:10.1038/s41467-022-28360-2. ISSN 2041-1723. PMC 8813914. PMID 35115561.
  25. ^ Sehovic, Emir; Hadrovic, Adem; Dogan, Senol (2019-11-10). "Detection and analysis of stable and flexible genes towards a genome signature framework in cancer". Bioinformation. 15 (10): 772–779. doi:10.6026/97320630015772. ISSN 0973-2063. PMC 6900328. PMID 31831960.
  26. ^ Ida, Vänttinen (2020). "Drug Response and Disease Progression Associated MicroRNAs in Multiple Myeloma". {{cite journal}}: Cite journal requires |journal= (help)
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