MROH9

MROH9 is also known as C1orf129 and ARMC11 (armadillo repeat-containing 11).{{cite web | work = NCBI (National Center for Biotechnology Information) | title = Homo sapiens MROH9 gene | url = https://www.ncbi.nlm.nih.gov/gene/80133 }}{{cite web | work = GeneCards | title = MROH9 gene | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=MROH9 }} The genomic location is on chromosome 1 (1q24.3) on its plus end, spanning 129,232 base pairs.

File:MROH9 Gene Locus.png

The MROH9 gene is encoded by an mRNA transcript that is 3,102 nucleotides in length. mRNA transcript variant 1 (NM_001163629.2), which encodes protein isoform 1 (NP_001157101.1), is the longest transcript encoding the longest, highest-quality isoform. Transcript variant 2 is found to have a shorter, more distant C-terminus, and an alternative 3’ coding region and 3’ UTR compared to variant 1. Transcript variant 1 has 23 exons, making up a coding sequence that is 2,586 nucleotides long.

File:MROH9 Annotated Conceptual Translation.png

The dominant isoform protein that the MROH9 encodes is isoform 1, with a length of 861 amino acids. Table 1 displays some of the other common protein isoforms of the MROH9.

Of the 11 MROH genes in the family, all of their respective proteins contain HEAT repeats, a type of protein structural motif made up of a short loop linking two alpha helices. HEAT repeats, structurally related to armadillo repeats, are known to form superhelical structures involved in intracellular transport. Protein isoform 1 encoded by the MROH9 gene has 5 HEAT regions and 2 HEAT repeats; the quantity of these vary across the different isoforms, as seen in the table.{{citation needed|date=December 2022}}

File:MROH9 Strict Ortholog Multiple Sequence Alignment.png

The secondary structure of human MROH9 protein isoform 1 has 49 alpha helices with no apparent sheets or coils. The I-TASSER result displaying the tertiary structure with the highest probability score is pictured at the top of the page, and this structure was seen across orthologs, as well.{{Cite web |title=I-TASSER results |url=https://seq2fun.dcmb.med.umich.edu//I-TASSER/output/S711851/ |access-date=2022-12-16 |website=seq2fun.dcmb.med.umich.edu}}

File:MROH9 Allen Mouse Brain Atlas.png

The encoded transcript of MRO genes were found in one study to exhibit “sexual dimorphic expression during murine gonadal development.” The researchers also found increased expression of MRO genes in human testicular tissue, and a particular cytoplasmic expression pattern of the protein in testicular germ cells.

RNAseq data from NCBI Gene shows that MROH9 in humans is only consistently expressed in the lungs and no other tissue, though it shows notable expression in the intestines, stomach, and male/female gonads in almost all of the sets. Low probability scores imply that this gene might be expressed at very low levels. Microarray-assessed tissue expression pattern data from confirms that expression is higher in the lungs, though very low across all other various tissues. Conditional expression pattern data shows that MROH9 is not particularly expressed in any one condition over the other.

The Allen Mouse Brain Atlas confirm the gene's expression in lung, intestine, and gonad tissue. MROH9 expression specifically correlates with a cluster that specializes in cilium organization and cilia cells. The Allen Mouse Brain Atlas also shows that the gene shows significant levels of expression in the olfactory bulb region of the brain. Since the lung, gonads, intestines, and nose all require cilia cells to function, it is possible that the MROH9 gene confers the function of such tissues.

File:MROH9 Protein Schematic.png

Subcellular localization of the MROH9 isoform 1 protein is predicted to be within the cytoplasm.{{Cite web |title=PSORT II Prediction |url=https://psort.hgc.jp/form2.html |access-date=2022-12-16 |website=psort.hgc.jp}} This is consistent across strict and distant orthologs, too, as the MROH9 protein shows cytoplasmic subcellular localization across most mammalian taxons. However, predicted data report that the protein could be important in the mitochondria, endoplasmic reticulum, and Golgi apparatus.

Predicted post-translational modifications reported by MyHits Motif Scan show that the MROH9 protein may have 27 phosphorylation sites, 7 N-linked glycosylation sites, and 4 myristoylation sites. However, considering that the probability scores are very low and that this protein is most probably located in the cytoplasm - meaning that it does not travel across membranes - predicted N-linked glycosylation and myristoylation sites are likely null. Phosphorylation is the only likely modification that can occur for this protein, but only a small handful of the predicted sites are conserved across MROH9 orthologs. Other phosphorylation sites, along with all the predicted N-linked glycosylation and myristoylation sites, are quite poorly conserved across orthologs.{{Cite web |title=Motif Scan |url=https://myhits.sib.swiss/cgi-bin/motif_scan |access-date=2022-12-16 |website=myhits.sib.swiss |language=en}} Predicted eukaryotic linear motifs (ELMs) show several matched sequences for cleavage sites, implying that the MROH9 protein sequence might be cleaved as part of its function.

Interestingly, MROH9 orthologs were observed to only be found in mammalian species, as seen in the table. Absolutely no homologs or orthologs were found in any birds, reptiles, amphibians, invertebrates, fungi, plants, or bacteria. Orthologs could be found in every extant mammalian species with the exception of Monotremes, which only showed homologs for different isoforms and various paralogs. It also appears that there is no direct correlation between estimated date of divergence and sequence similarity with humans; orthologs found in animals in the Glires taxon (which diverged most recently in mammals) showed less similarity to the human MROH9 sequence compared to mammal groups that diverged longer ago.

MROH7 is a notable paralog of the MROH9 gene and is found in humans as well as some other select mammal species. The second table above shows some of these paralogs and their sequence identity and similarity to the human MROH7 gene. Human MROH7 was found to have a 22% shared sequence identity to the human MROH9 gene.

File:Corrected sequence divergence versus median date of divergence of MROH9.png

The graph to the right shows the corrected sequence divergence versus median date of divergence of MROH9. Plotted with the rate of evolution of MROH9 are rates for fibrinogen alpha (a rapidly evolving gene), cytochrome C (a slowly evolving gene), and the MROH7 paralog.{{cite journal | vauthors = Kant JA, Fornace AJ, Saxe D, Simon MI, McBride OW, Crabtree GR | title = Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 8 | pages = 2344–2348 | date = April 1985 | pmid = 2986113 | pmc = 397554 | doi = 10.1073/pnas.82.8.2344 | doi-access = free | bibcode = 1985PNAS...82.2344K }}{{cite journal | vauthors = Dickerson RE | title = The structures of cytochrome c and the rates of molecular evolution | journal = Journal of Molecular Evolution | volume = 1 | issue = 1 | pages = 26–45 | date = 1971-03-01 | pmid = 4377446 | doi = 10.1007/BF01659392 | s2cid = 24992347 | bibcode = 1971JMolE...1...26D }} The graph shows that the slope for MROH7 evolution is much lower than MROH9, with its rate of divergence being almost similar to that of cytochrome C. All of the orthologs of the MROH7 gene show the same sequence identity despite having diverged at different times in history. This could imply that the orthologs for the MROH7 gene are closer related together, and might have diverged from MROH9 roughly 94 million years ago and did not evolve much since then. It is also possible that the MROH7 paralog is evolving slower than the MROH9 gene.{{Cite web |title=MROH7 maestro heat like repeat family member 7 [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=374977 |access-date=2022-12-16 |website=www.ncbi.nlm.nih.gov}}

Both GLO1 and RNF123 appear in several databases and articles, heightening the possibility of these being genuine interacting proteins for MROH9.{{cite journal | vauthors = Huttlin EL, Bruckner RJ, Navarrete-Perea J, Cannon JR, Baltier K, Gebreab F, Gygi MP, Thornock A, Zarraga G, Tam S, Szpyt J, Gassaway BM, Panov A, Parzen H, Fu S, Golbazi A, Maenpaa E, Stricker K, Guha Thakurta S, Zhang T, Rad R, Pan J, Nusinow DP, Paulo JA, Schweppe DK, Vaites LP, Harper JW, Gygi SP | display-authors = 6 | title = Dual proteome-scale networks reveal cell-specific remodeling of the human interactome | journal = Cell | volume = 184 | issue = 11 | pages = 3022–3040.e28 | date = May 2021 | pmid = 33961781 | pmc = 8165030 | doi = 10.1016/j.cell.2021.04.011 }}{{cite journal | vauthors = Khanna R, Krishnamoorthy V, Parnaik VK | title = E3 ubiquitin ligase RNF123 targets lamin B1 and lamin-binding proteins | journal = The FEBS Journal | volume = 285 | issue = 12 | pages = 2243–2262 | date = June 2018 | pmid = 29676528 | doi = 10.1111/febs.14477 | s2cid = 4997525 | doi-access = free }} RNF123 and PARK2, another interacting protein, are both E3 Ubiquitin ligases, which are responsible for targeting proteins for degradation.{{cite journal | vauthors = Sun X, Shu Y, Ye G, Wu C, Xu M, Gao R, Huang D, Zhang J | display-authors = 6 | title = Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy | journal = Acta Pharmaceutica Sinica B | volume = 12 | issue = 2 | pages = 838–852 | date = February 2022 | pmid = 35256949 | pmc = 8897022 | doi = 10.1016/j.apsb.2021.07.003 }} GLO1, or lactoylglutathione ligase, is an enzyme catalyzing isomerization of hemithioacetal adducts.{{Cite web |title=GLO1 Gene - GeneCards {{!}} LGUL Protein {{!}} LGUL Antibody |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=GLO1 |access-date=2022-12-16 |website=www.genecards.org}} These results explain that MROH9 function may depend on the activity of these ligases and might be degraded.

MROH9 appears in several publications indicating its potential role as an oncogene in various types of cancers. One paper found that there was excessive chromatin looping near MROH9 and several FMO genes (gene neighbors to MROH9 on chromosome 1), along with other key oncogenes in nasopharyngeal cancer, potentially linking MROH9 with oncogene properties.{{cite journal | vauthors = Animesh S, Choudhary R, Wong BJ, Koh CT, Ng XY, Tay JK, Chong WQ, Jian H, Chen L, Goh BC, Fullwood MJ | display-authors = 6 | title = Profiling of 3D Genome Organization in Nasopharyngeal Cancer Needle Biopsy Patient Samples by a Modified Hi-C Approach | journal = Frontiers in Genetics | volume = 12 | pages = 673530 | date = 2021 | pmid = 34539729 | pmc = 8446523 | doi = 10.3389/fgene.2021.673530 | doi-access = free }}{{cite journal | vauthors = Uno Y, Shimizu M, Yamazaki H | title = Molecular and functional characterization of flavin-containing monooxygenases in cynomolgus macaque | journal = Biochemical Pharmacology | volume = 85 | issue = 12 | pages = 1837–1847 | date = June 2013 | pmid = 23623750 | doi = 10.1016/j.bcp.2013.04.012 }} MROH9 has also been found to play roles as an oncogene in other forms of cancer; studies have found it to be a potential necroptosis-related gene that is overexpressed in high-risk groups for pancreatic adenocarcinoma.{{cite journal | vauthors = Wu Z, Huang X, Cai M, Huang P, Guan Z | title = Novel necroptosis-related gene signature for predicting the prognosis of pancreatic adenocarcinoma | journal = Aging | volume = 14 | issue = 2 | pages = 869–891 | date = January 2022 | pmid = 35077391 | pmc = 8833111 | doi = 10.18632/aging.203846 }}{{cite journal | vauthors = Lu J, Yu C, Bao Q, Zhang X, Wang J | title = Identification and analysis of necroptosis-associated signatures for prognostic and immune microenvironment evaluation in hepatocellular carcinoma | journal = Frontiers in Immunology | volume = 13 | pages = 973649 | date = 2022 | pmid = 36081504 | pmc = 9445885 | doi = 10.3389/fimmu.2022.973649 | doi-access = free }} MROH9 has been further confirmed by some studies as an oncogene for breast cancers, with alterations in chromosome 1 being described in over half of breast cancer tumors. A large number of copy number variations (CNVs) are particularly found on the 1q arm of chromosome 1 where MROH9 is found.{{cite journal | vauthors = Rodrigues-Peres RM, de Carvalho BS, Anurag M, Lei JT, Conz L, Gonçalves R, Cardoso Filho C, Ramalho S, de Paiva GR, Derchain SF, Lopes-Cendes I, Ellis MJ, Sarian LO | display-authors = 6 | title = Copy number alterations associated with clinical features in an underrepresented population with breast cancer | journal = Molecular Genetics & Genomic Medicine | volume = 7 | issue = 7 | pages = e00750 | date = July 2019 | pmid = 31099189 | pmc = 6625096 | doi = 10.1002/mgg3.750 }} Other research found MROH9 to be a predicted target of miR-3646, a type of microRNA that promotes cell proliferation in human breast cancer cells.{{cite journal | vauthors = Tao S, Liu YB, Zhou ZW, Lian B, Li H, Li JP, Zhou SF | title = miR-3646 promotes cell proliferation, migration, and invasion via regulating G2/M transition in human breast cancer cells | journal = American Journal of Translational Research | volume = 8 | issue = 4 | pages = 1659–1677 | date = 2016-04-15 | pmid = 27186291 | pmc = 4859896 }} In addition to this, MROH9 is also found at a chromosome 1 locus that is associated with central corneal thickness, a measure of glaucoma. It is found at the associated locus together with PRRX1, another gene that, along with MROH9, was also found to be an associated variant in systemic lupus erythematosus{{cite journal | vauthors = Choquet H, Melles RB, Yin J, Hoffmann TJ, Thai KK, Kvale MN, Banda Y, Hardcastle AJ, Tuft SJ, Glymour MM, Schaefer C, Risch N, Nair KS, Hysi PG, Jorgenson E | display-authors = 6 | title = A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness | journal = Communications Biology | volume = 3 | issue = 1 | pages = 301 | date = June 2020 | pmid = 32528159 | pmc = 7289804 | doi = 10.1038/s42003-020-1037-7 }}{{cite journal | vauthors = Wang YF, Zhang Y, Lin Z, Zhang H, Wang TY, Cao Y, Morris DL, Sheng Y, Yin X, Zhong SL, Gu X, Lei Y, He J, Wu Q, Shen JJ, Yang J, Lam TH, Lin JH, Mai ZM, Guo M, Tang Y, Chen Y, Song Q, Ban B, Mok CC, Cui Y, Lu L, Shen N, Sham PC, Lau CS, Smith DK, Vyse TJ, Zhang X, Lau YL, Yang W | display-authors = 6 | title = Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups | journal = Nature Communications | volume = 12 | issue = 1 | pages = 772 | date = February 2021 | pmid = 33536424 | pmc = 7858632 | doi = 10.1038/s41467-021-21049-y | bibcode = 2021NatCo..12..772W }}

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Category:Genes on human chromosome 1