Transport and golgi organization 2 homolog (TANGO2) also known as chromosome 22

open reading frame In molecular biology, reading frames are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible reading frames ...

25 (C22orf25) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

sequence of (N)-

Asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

(R)-

Arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...

(D)-

Aspartic Acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...

(E)-

Glutamic Acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α- amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can ...

. This domain is found among distantly related

species A species () is often defined as the largest group of organisms in which any two individuals of the appropriate sexes or mating types can produce fertile offspring, typically by sexual reproduction. It is the basic unit of Taxonomy (biology), ...

from the six kingdoms:

Eubacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among the ...

Archaebacteria Archaea ( ) is a domain of organisms. Traditionally, Archaea only included its prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even though the domain Archaea cladis ...

Protista A protist ( ) or protoctist is any Eukaryote, eukaryotic organism that is not an animal, Embryophyte, land plant, or fungus. Protists do not form a Clade, natural group, or clade, but are a Paraphyly, paraphyletic grouping of all descendants o ...

Fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...

Plantae Plants are the eukaryotes that form the kingdom Plantae; they are predominantly photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with cyanobacteria to produce sugars fro ...

, and

Animalia Animals are multicellular, eukaryotic organisms in the Biology, biological Kingdom (biology), kingdom Animalia (). With few exceptions, animals heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, ...

and is known to be involved in Golgi organization and protein secretion. It is likely that it localizes in the

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

but is anchored in the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

by the second amino acid. C22orf25 is also

xenolog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...

ous to T10 like proteins in the Fowlpox Virus and Canarypox Virus. The gene coding for C22orf25 is located on

chromosome 22 Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 51 million DNA base pairs and representing b ...

and the location q11.21, so it is often associated with

22q11.2 deletion syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent i ...

Protein

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 A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

and ending at 20,053,447 base pairs. There is a 1.5-3.0 Mb deletion containing around 30-40

genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

, spanning this region that causes the most survivable genetic deletion disorder known as

, which is most commonly known as DiGeorge syndrome or Velocaridofacial syndrome. 22q11.2 deletion syndrome has a vast array of

phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological properti ...

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). Gene Neighborhood of C22orf25

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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

interactions.

Transcription factors

Some of the main transcription factors that bind to the promoter are listed below.

Expression analysis

Expression data from

Expressed Sequence Tag In genetics, an expressed sequence tag (EST) is a short sub-sequence of a cDNA sequence. ESTs may be used to identify gene transcripts, and were instrumental in gene discovery and in gene-sequence determination. The identification of ESTs has pro ...

mapping,

microarray A microarray is a multiplex (assay), multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of biological interactions. It is a two-dimensional array on a Substrate (materials science), solid substrate—usu ...

and ''in situ'' hybridization show high expression for ''Homo sapiens'' in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

and nerves. Expression is not restricted to these areas and low expression is seen elsewhere in the body. In ''

Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a Hybrid word, blend of the Greek ''caeno-'' (recent), ''r ...

'', 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.

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 Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

(C-mannosylation),

glycation Glycation (non-enzymatic glycosylation) is the covalent bond, covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is th ...

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

(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 Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the ''RELA'' gene. RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear tra ...

, RELB, BTRC, RPS27A, BCL3, MAP3K8, NFKBIA,

SIN3A Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the ''SIN3A'' gene. Function The protein encoded by this gene is a transcriptional regulatory protein. It contains paired amphipathic helix (PAH) domains, whic ...

SUMO1 Small ubiquitin-related modifier 1 is a protein that in humans is encoded by the ''SUMO1'' gene. Function This gene encodes a protein that is a member of the SUMO (small ubiquitin-like modifier) protein family. It is a ubiquitin-like protein a ...

, Tat.

Clinical significance

Mutations in the TANGO2 gene may cause defects in mitochondrial β-oxidation and increased

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

stress and a reduction in Golgi volume density. These mutations results in early onset

hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

hyperammonemia Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. Severe hyperammonemia is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammoni ...

rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...

cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beat ...

s, and

encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

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.

References

External links

{{Webarchive, url=https://web.archive.org/web/20171107005221/https://www.tango2.it/ , date=2017-11-07 www.tango2.it - Disease website

www.tango2research.org - Research disease website -