TANGO2

The C22orf25 gene is located on the long arm (q) of chromosome 22 in region 1, band 1, and sub-band 2 (22q11.21) starting at 20,008,631 base pairs and ending at 20,053,447 base pairs. There is a 1.5-3.0 Mb deletion containing around 30-40 genes, spanning this region that causes the most survivable genetic deletion disorder known as 22q11.2 deletion syndrome, which is most commonly known as DiGeorge syndrome or Velocaridofacial syndrome.{{cite journal | vauthors = Meechan DW, Maynard TM, Tucker ES, LaMantia AS | title = Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: Patterning, proliferation, and mitochondrial functions of 22q11 genes | journal = International Journal of Developmental Neuroscience | volume = 29 | issue = 3 | pages = 283–294 | year = 2011 | pmid = 20833244 | doi = 10.1016/j.ijdevneu.2010.08.005 | pmc=3770287}}{{cite web | vauthors = Kniffin C | title = DiGeorge Syndrome; DGS. Retrieved April 2012, from Online Mendelian Inheritance in Man | url=http://omim.org/entry/188400 }} 22q11.2 deletion syndrome has a vast array of phenotypes and is not attributed to the loss of a single gene. The vast phenotypes arise from deletions of not only DiGeorge Syndrome Critical Region (DGCR) genes and disease genes but other unidentified genes as well.{{cite journal | vauthors = Scambler PJ | title = The 22q11 deletion syndromes | journal = Hum. Mol. Genet. | volume = 9 | issue = 16 | pages = 2421–6 | year = 2000 | pmid = 11005797 | doi = 10.1093/hmg/9.16.2421 | doi-access = free }}

C22orf25 is in close proximity to DGCR8 as well as other genes known to play a part in DiGeorge Syndrome such as armadillo repeat gene deleted in Velocardiofacial syndrome (ARVCF), Cathechol-O-methyltransferase (COMT) and T-box 1 (TBX1).{{cite web | title = 22q11.2 Deletion Syndrome | url = https://www.ncbi.nlm.nih.gov/books/NBK1523/ | publisher = University of Washington, Seattle | year = 1993 | pmid = 20301696 | last1 = Adam | first1 = M. P. | last2 = Feldman | first2 = J. | last3 = Mirzaa | first3 = G. M. | last4 = Pagon | first4 = R. A. | last5 = Wallace | first5 = S. E. | author6 = Bean LJH | last7 = Gripp | first7 = K. W. | last8 = Amemiya | first8 = A. | last9 = McDonald-Mcginn | first9 = D. M. | last10 = Hain | first10 = H. S. | last11 = Emanuel | first11 = B. S. | last12 = Zackai | first12 = E. H. }}{{cite web | title=BLAT UCSC Genome Browser|url=http://genome.ucsc.edu/cgi-bin/hgBlat?hgsid=248121649}}

File:Gene Neighborhood of C22orf25.gif

The promoter for the C22orf25 gene spans 687 base pairs from 20,008,092 to 20,008,878 with a predicted transcriptional start site that is 104 base pairs and spans from 20,008,591 to 20,008,694.{{cite web|title=El Durado (Genomatix)|url=http://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=651b17c55e64c2421b0e1bb8d7b4d89b}} The promoter region and beginning of the C22orf25 gene (20,008,263 to 20,009,250) is not conserved past primates. This region was used to determine transcription factor interactions.

Some of the main transcription factors that bind to the promoter are listed below.{{cite web|title=El Durado-Genomatix|url=http://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=651b17c55e64c2421b0e1bb8d7b4d89b}}

Expression data from Expressed Sequence Tag mapping, microarray and in situ hybridization show high expression for Homo sapiens in the blood, bone marrow and nerves.{{cite web|title=Unigene NCBI|url=http://www.ncbi.nim.nih.gov/|access-date=2012-04-26|archive-url=https://web.archive.org/web/20130712201927/http://ncbi.nim.nih.gov/|archive-date=2013-07-12|url-status=dead}}{{cite web|title=GEO Profiles NCBI|url=https://www.ncbi.nlm.nih.gov/}}{{cite web|title=Bio GPS|url=http://biogps.org/#goto=genereport&id=128989}} Expression is not restricted to these areas and low expression is seen elsewhere in the body. In Caenorhabditis elegans, the snt-1 gene (C22orf25 homologue) was expressed in the nerve ring, ventral and dorsal cord processes, sites of neuromuscular junctions, and in neurons.{{cite web|title=WormBase|url=http://www.wormbase.org/}}

The NRDE (DUF883) domain, is a domain of unknown function spanning majority of the C22orf25 gene and is found among distantly related species, including viruses.

Post translational modifications of the C22orf25 gene that are evolutionarily conserved in the Animalia and Plantae kingdoms as well as the Canarypox Virus include glycosylation (C-mannosylation),{{cite web|title=NetCGly (ExPASy)|url=http://expasy.org/tools|access-date=2012-04-28|archive-date=2012-04-24|archive-url=https://web.archive.org/web/20120424105623/http://expasy.org/tools|url-status=dead}} glycation,{{cite web|title=NetGlycate (ExPASy)|url=http://expasy.org/tools|access-date=2012-04-28|archive-date=2012-04-24|archive-url=https://web.archive.org/web/20120424105623/http://expasy.org/tools|url-status=dead}} phosphorylation (kinase specific),{{cite web|title=Phos (ExPASy)|url=http://expasy.org/tools|access-date=2012-04-28|archive-date=2012-04-24|archive-url=https://web.archive.org/web/20120424105623/http://expasy.org/tools|url-status=dead}} and palmitoylation.{{cite web|title=CSS Palm (ExPASy)|url=http://expasy.org/tools|access-date=2012-04-28|archive-date=2012-04-24|archive-url=https://web.archive.org/web/20120424105623/http://expasy.org/tools|url-status=dead}}

C22orf25 localizes to the cytoplasm and is anchored to the cell membrane by the second amino acid. As mentioned previously, the second amino acid is modified by palmitoylation. Palmitoylation is known to contribute to membrane association{{cite journal | vauthors = Resh MD | title = Palmitoylation of Ligands, Receptors, and Intracellular Signaling Molecules | journal = Science's STKE | issue = 359 | pages = 14 | year = 2006 | pmid = 17077383 | doi = 10.1126/stke.3592006re14 | volume=2006| s2cid = 25729573 }} because it contributes to enhanced hydrophobicity. Palmitoylation is known to play a role in the modulation of proteins' trafficking,{{cite journal | vauthors = Draper JM, Xia Z, Smith CD | title = Cellular palmitoylation and trafficking of lipated peptides | journal = Journal of Lipid Research| volume = 48 | issue = 8 | pages = 1873–1884 | date = Aug 2007 | pmid = 17525474 | doi = 10.1194/jlr.m700179-jlr200 |doi-access=free | pmc=2895159}} stability{{cite journal | vauthors = Linder ME, Deschenes RJ | title = Palmitoylation: policing protein stability and traffic | journal = Nature Reviews Molecular Cell Biology | volume = 8 | issue = 1 | pages = 74–84 | date = Jan 2007 | pmid = 17183362 | doi = 10.1038/nrm2084 | s2cid = 26339042 }} and sorting.{{cite journal | vauthors = Greaves J, Chamberlain LH | title = Palmitoylation-dependent protein sorting | journal = The Journal of Cell Biology| volume = 176 | issue = 3 | pages = 249–254 | date = Jan 2007 | pmid = 17242068 | doi = 10.1083/jcb.200610151 | pmc=2063950}} Palmitoylation is also involved in cellular signaling{{cite journal | vauthors = Casey PJ | title = Protein lipidation in cell signaling | journal = Science | volume = 268 | issue = 5208 | pages = 221–5 | year = 1995 | pmid = 7716512 | doi = 10.1126/science.7716512 | bibcode = 1995Sci...268..221C }} and neuronal transmission.{{cite journal | vauthors = Roth AF, Wan J, Bailey AO, Sun B, Kuchar JA, Green WN, Phinney BS, Yates JR, Davis NG | title = Global analysis of protein palmitoylation in yeast | journal = Cell | volume = 125 | issue = 5 | pages = 1003–1013 | date = June 2006 | pmid = 16751107 | doi = 10.1016/j.cell.2006.03.042 | pmc=2246083}}

C22orf25 has been shown to interact with NFKB1,{{cite web|title=Molecular Interaction Database|url=http://mint.bio.uniroma2.it/mint/Welcome.do|url-status=dead|archiveurl=https://web.archive.org/web/20060506110418/http://mint.bio.uniroma2.it/mint/Welcome.do|archivedate=2006-05-06}} RELA, RELB, BTRC, RPS27A, BCL3, MAP3K8, NFKBIA, SIN3A, SUMO1, Tat.{{cite web|title=Viral Molecular Interaction Database|url=http://mint.bio.uniroma2.it/virusmint/Welcome.do|url-status=dead|archiveurl=https://web.archive.org/web/20150215025855/http://mint.bio.uniroma2.it/virusmint/Welcome.do|archivedate=2015-02-15}}

Mutations in the TANGO2 gene may cause defects in mitochondrial β-oxidation{{cite journal | vauthors = Kremer LS, Distelmaier F, Alhaddad B, Hempel M, Iuso A, Küpper C, Mühlhausen C, Kovacs-Nagy R, Satanovskij R, Graf E, Berutti R, Eckstein G, Durbin R, Sauer S, Hoffmann GF, Strom TM, Santer R, Meitinger T, Klopstock T, Prokisch H, Haack TB | display-authors = 6 | title = Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy | journal = American Journal of Human Genetics | volume = 98 | issue = 2 | pages = 358–62 | year = 2016 | pmid = 26805782 | pmc = 4746337 | doi = 10.1016/j.ajhg.2015.12.009 }} and increased endoplasmic reticulum stress and a reduction in Golgi volume density.{{cite journal | vauthors = Lalani SR, Liu P, Rosenfeld JA, Watkin LB, Chiang T, Leduc MS, Zhu W, Ding Y, Pan S, Vetrini F, Miyake CY, Shinawi M, Gambin T, Eldomery MK, Akdemir ZH, Emrick L, Wilnai Y, Schelley S, Koenig MK, Memon N, Farach LS, Coe BP, Azamian M, Hernandez P, Zapata G, Jhangiani SN, Muzny DM, Lotze T, Clark G, Wilfong A, Northrup H, Adesina A, Bacino CA, Scaglia F, Bonnen PE, Crosson J, Duis J, Maegawa GH, Coman D, Inwood A, McGill J, Boerwinkle E, Graham B, Beaudet A, Eng CM, Hanchard NA, Xia F, Orange JS, Gibbs RA, Lupski JR, Yang Y | display-authors = 6 | title = Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations | journal = American Journal of Human Genetics | volume = 98 | issue = 2 | pages = 347–57 | year = 2016 | pmid = 26805781 | pmc = 4746334 | doi = 10.1016/j.ajhg.2015.12.008 }} These mutations results in early onset hypoglycemia, hyperammonemia, rhabdomyolysis, cardiac arrhythmias, and encephalopathy that later develops into cognitive impairment. Abnormal autophagy and mitophagy have been associated with TANGO2-related disease and may explain the varying presentation in muscle biopsies, including secondary abnormal fatty acid and mitochondrial metabolism.{{Cite journal |last=de Calbiac |first=Hortense |last2=Montealegre |first2=Sebastian |last3=Straube |first3=Marjolène |last4=Renault |first4=Solène |last5=Debruge |first5=Hugo |last6=Chentout |first6=Loïc |last7=Ciura |first7=Sorana |last8=Imbard |first8=Apolline |last9=Le Guillou |first9=Edouard |last10=Marian |first10=Anca |last11=Goudin |first11=Nicolas |last12=Caccavelli |first12=Laure |last13=Fabrega |first13=Sylvie |last14=Hubas |first14=Arnaud |last15=van Endert |first15=Peter |date=February 2024 |title=TANGO2-related rhabdomyolysis symptoms are associated with abnormal autophagy functioning |url=http://dx.doi.org/10.1080/27694127.2024.2306766 |journal=Autophagy Reports |volume=3 |issue=1 |doi=10.1080/27694127.2024.2306766 |issn=2769-4127|pmc=7617261 }}

{{Reflist|33em}}

• [https://www.tango2.it] {{Webarchive|url=https://web.archive.org/web/20171107005221/https://www.tango2.it/ |date=2017-11-07 }} www.tango2.it - Disease website
• [http://tango2research.org] www.tango2research.org - Research disease website -