# TANGO2

Transport and golgi organization 2 homolog (TANGO2) also known as chromosome 22 open reading frame 25 (C22orf25) is a protein that in humans is encoded by the TANGO2 gene.
The function of C22orf25 is not currently known. It is characterized by the NRDE superfamily domain (DUF883), which is strictly known for the conserved amino acid sequence of (N)-Asparagine (R)-Arginine (D)-Aspartic Acid (E)-Glutamic Acid. This domain is found among distantly related species from the six kingdoms: Eubacteria, Archaebacteria, Protista, Fungi, Plantae, and Animalia and is known to be involved in Golgi organization and protein secretion. It is likely that it localizes in the cytoplasm but is anchored in the cell membrane by the second amino acid. C22orf25 is also xenologous to T10 like proteins in the Fowlpox Virus and Canarypox Virus. The gene coding for C22orf25 is located on chromosome 22 and the location q11.21, so it is often associated with 22q11.2 deletion syndrome.

## Protein

| Gene Size | Protein Size | # of exons | Promoter Sequence | Signal Peptide | Molecular Weight | Domain Length |
| 2271 bp | 276 aa | 9 | 687 bp | No | 30.9 kDa | 270 aa |

## Gene neighborhood

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. 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.
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).

## Predicted mRNA features
### Promoter

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. 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.

### Transcription factors

Some of the main transcription factors that bind to the promoter are listed below.
| Reference | Detailed Family Information | Start (amino acid) | End (amino acid) | Strand |
| XBBF | X-box binding factors | 227 | 245 | - |
| GCMF | Chorion-specific transcription factors (with a GCM DNA binding domain) | 151 | 165 | - |
| YBXF | Y-box binding transcription factors | 158 | 170 | - |
| RUSH | SWI/SNF related nucleophosphoproteins (with a RING finger binding motif) | 222 | 232 | - |
| NEUR | NeuroD, Beta2, HLH domain | 214 | 226 | - |
| PCBE | PREB core-binding element | 148 | 162 | - |
| NR2F | Nuclear receptor subfamily 2 factors | 169 | 193 | - |
| AP1R | MAF and AP1 related factors | 201 | 221 | - |
| ZF02 | C2H2 zinc finger transcription factors 2 | 108 | 130 | - |
| TALE | TALE homeodomain class recognizing TG motifs | 216 | 232 | - |
| WHNF | Winged helix transcription factors | 271 | 281 | - |
| FKHD | Forkhead domain factors | 119 | 135 | + |
| MYOD | Myoblast determining factors | 218 | 234 | + |
| AP1F | AP1, activating protein 1 | 118 | 130 | + |
| BCL6 | POZ domain zinc finger expressed in B cells | 190 | 206 | + |
| CARE | Calcium response elements | 196 | 206 | + |
| EVI1 | EVI1 nuclear transcription factor | 90 | 106 | + |
| ETSF | ETS transcription factor | 162 | 182 | + |
| TEAF | TEA/ATTS DNA binding domain factors | 176 | 188 | + |

## Expression analysis

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. 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.

## Evolutionary history

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.
| Genus and Species | Common Name | Accession Number | Seq. Length | Seq. Identity | Seq. Similarity | Kingdom | Time of Divergence |
| Homo sapiens | humans | NP_690870.3 | 276aa | - | - | Animalia | - |
| Pan troglodytes | common chimpanzee | BAK62258.1 | 276aa | 99% | 100% | Animalia | 6.4 mya |
| Ailuropoda melanoleuca | giant panda | XP_002920626 | 276aa | 91% | 94% | Animalia | 94.4 mya |
| Mus musculus | house mouse | NP_613049.2 | 276aa | 88% | 95% | Animalia | 92.4 mya |
| Meleagris gallopavo | turkey | XP_003210928 | 276aa | 74% | 88% | Animalia | 301.7 mya |
| Gallus gallus | Red Junglefowl | NP_001007837 | 276aa | 73% | 88% | Animalia | 301.7 mya |
| Xenopus laevis | African clawed frog | NP_001083694 | 275aa | 69% | 86% | Animalia | 371.2 mya |
| Xenopus (Silurana) tropicalis | Western clawed frog | NP_001004885.1 | 276aa | 68% | 85% | Animalia | 371.2 mya |
| Salmo salar | Atlantic salmon | NP_001167100 | 274aa | 66% | 79% | Animalia | 400.1 mya |
| Danio rerio | zebrafish | NP_001003781 | 273aa | 64% | 78% | Animalia | 400.1 mya |
| Canarypox | virus | NP_955117 | 275aa | 50% | 69% | - | - |
| Fowlpox | virus | NP_039033 | 273aa | 44% | 63% | - | - |
| Cupriavidus | proteobacteria | YP_002005507.1 | 275aa | 38% | 52% | Eubacteria | 2313.2 mya |
| Burkholderia | proteobacteria | YP_004977059 | 273aa | 37% | 53% | Eubacteria | 2313.2 mya |
| Physcomitrella patens | moss | XP_001781807 | 275aa | 37% | 54% | Plantae | 1369 mya |
| Zea mays | maize/corn | ACG35095 | 266aa | 33% | 53% | Plantae | 1369 mya |
| Trichophyton rubrum | fungus | XP_003236126 | 306aa | 32% | 47% | Fungi | 1215.8 mya |
| Sporisorium reilianum | Plant pathogen | CBQ69093 | 321aa | 32% | 43% | Fungi | 1215.8 mya |
| Perkinsus marinus | pathogen of oysters | XP_002787624 | 219aa | 31% | 48% | Protista | 1381.2 mya |
| Tetrahymena thermophilia | Ciliate protozoa | XP_001010229 | 277aa | 26% | 44% | Protista | 1381.2 mya |
| Natrialba magadii | extremophile | YP_003481665 | 300aa | 25% | 39% | Archaebacteria | 3556.3 mya |
| Halopiger xanaduensis | halophilic archaeon | YP_004597780.1 | 264aa | 24% | 39% | Archaebacteria | 3556.3 mya |

## Predicted protein features
### Post translational modifications

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), glycation, phosphorylation (kinase specific), and palmitoylation.

### Predicted topology

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 because it contributes to enhanced hydrophobicity. Palmitoylation is known to play a role in the modulation of proteins' trafficking, stability and sorting. Palmitoylation is also involved in cellular signaling and neuronal transmission.

### Protein Interactions

C22orf25 has been shown to interact with NFKB1, RELA, RELB, BTRC, RPS27A, BCL3, MAP3K8, NFKBIA, SIN3A, SUMO1, Tat.

## Clinical significance

Mutations in the TANGO2 gene may cause defects in mitochondrial β-oxidation and increased endoplasmic reticulum stress and a reduction in Golgi volume density. 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.