DOP1B

DOP1B is a human gene located just above the Down Syndrome chromosomal region (DSCR) located at 21p22.2 sub-band. Although the exact function of this gene is not yet fully understood, it has been proven to play a role in multiple biological processes, and its over-expression (triplication) has been linked to multiple facets of the Down Syndrome phenotype, most notably mental retardation.

DOP1B
Identifiers
Aliases	DOP1B, 21orf5, C21orf5, dopey family member 2, DOPEY2, DOP1 leucine zipper like protein B
External IDs	OMIM: 604803; MGI: 1917278; HomoloGene: 21068; GeneCards: DOP1B; OMA:DOP1B - orthologs
Gene location (Human) Chr. Chromosome 21 (human) Band 21q22.12 Start 36,156,782 bp End 36,294,274 bp
Gene location (Mouse) Chr. Chromosome 16 (mouse) Band 16|16 C4 Start 93,508,792 bp End 93,607,478 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence rectum cerebellar cortex cerebellar hemisphere right hemisphere of cerebellum monocyte testicle minor salivary glands muscle of leg gastrocnemius muscle Top expressed in granulocyte epithelium of stomach superior frontal gyrus primary visual cortex cerebellar cortex dentate gyrus of hippocampal formation granule cell muscle of thigh duodenum secondary oocyte facial motor nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function molecular function Cellular component Golgi membrane extracellular exosome cytosol endosome trans-Golgi network Golgi apparatus membrane Biological process multicellular organism development protein transport cognition endoplasmic reticulum organization Golgi to endosome transport transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9980 70028 Ensembl ENSG00000142197 ENSMUSG00000022946 UniProt Q9Y3R5 Q3UHQ6 RefSeq (mRNA) NM_005128 NM_001320714 NM_026700 NM_027293 NM_001357118 RefSeq (protein) NP_001307643 NP_005119 NP_080976 NP_081569 NP_001344047 Location (UCSC) Chr 21: 36.16 – 36.29 Mb Chr 16: 93.51 – 93.61 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Gene

The DOP1B gene is located on human chromosome 21, at chromosome band 21q22.12. This band is located in open reading frame 5, hence the alias C21orf5. DOP1B gene is composed of 137,493 bases making up 37 exons and 39 distinct gt-ag introns, all located between CBR3 and KIAA0136 genes.

Transcription produces 10 unique mRNAs, 8 alternatively spliced variants, and 2 unspliced forms. These unique mRNAs differ by varying truncation of the 3' and 5' ends, as well as the presence of 3 cassette exons. These mRNA variants range from 7691bp (mRNA variant DOPEY2.aAug10) to 315bp (mRNA variant DOPEY2.jAug10-unspliced) and are further described in Table 1 below.

The mRNA expressed and levels of expression differ based on the location and tissue type in the body, but overall has been found to be expressed ubiquitously. The highest expression has been found in differentiating, rather than proliferating, tissue zones. Transcript was identified with the highest confidence in the erythroleukemia, placental cells and overall in the brain, and at a medium confidence level in the perirhinal cortex, medial temporal lobe, colon, as well in the salivary and adrenal glands.

Protein

Of the ten mRNAs produced, six of them are translated into viable proteins. Please see table above for more details. The largest, having a molecular weight of 258230 Da, and highest expressed protein, DOP1B.a, is composed of 2298 amino acids that make up an N-terminal domain, seven transmembrane domains, and a C-terminal coiled coil stretch that forms a leucine-like zipper domain. Like other leucine zippers domains, DOP1B's C-terminal is hypothesized to be involved in multiple protein-protein and transcription factor interactions. This indicates that DOP1B might act as a transcription co-activator; however, further research must be done to fully understand the precise physiological function.

Protein Interactions

Very little work has been done on understanding the intricacies of the protein interactions; however, STRING has identified direct links with three proteins: MON2, TRIP12, and HECTD1. DOP1B is also indirectly associated with the following proteins: ARL16, ATP9A, ARL1, ATP9B, UBE3A, HERC5, HERC4, HACE1, UBE3C, and UBR5. See Figure 2 for interactions.

Figure 2. Overview of direct protein interactions that have been experimentally determined. These interactions and relationships include gene fusions, co-occurrences, co-expressions, and homologies.

Homology

Phylogenesis suggest that DOP1B can be traced back to a common ancestor of animals and fungi due to its highly conserved C-terminal domain DOP1B has 84 known orthologs and 158 speciation nodes in the gene tree. The most similar orthologs being in the chimpanzee (Pan troglodytes), dog (Canis familiaris), cow (Bos Taurus), as well as the rat and mouse (Rattus norvegicus and Mus musculus).

The only known paralog is DOPEY1.

Sub-cellular localization

Gene Ontology (GO) has traced the DOP1B protein to 5 main areas: the Golgi membrane, the trans-Golgi network, cytosol, and extracellular endosome. COMPARTMENTS localization data places the highest confidence of localization to the extracellular exosome and the Golgi membrane.

Figure 1: Description of mRNA and Protein Variants:

mRNA Variant	Spliced mRNA Length	Protein Length	5' UTR	3' UTR	Unspliced pre-mRNA Length	Number of Exons	Tissue-mRNA Expression (no strict specificity implied)
aAug10	7691 bp	2298 aa	85 bp	709 bp	129746 bp	37	ubiquitous
bAug10	2173 bp	332aa		1174 bp	15610 bp	6	carcinoid, lung, colon, colon tumor, RER+
cAug10	742 bp	222 aa	74 bp		49789 bp	6	breast, t-lymphocytes
dAug10	623 bp	145 aa	188 bp		43664 bp	4	lung
eAug10	345 bp	114 aa			9925 bp	3	spleen
fAug10	571 bp	110 aa	241 bp		1322 bp	2	thalamus
gAug10	549 bp	non-coding	11 bp	499 bp	794 bp	2	spleen
hAug- unspliced	543 bp	non-coding	377 bp		543 bp	1	stomach
iAug10	514 bp	non-coding	205 bp	204 bp	7377 bp	2	thyroid gland
jAug10- unspliced	315 bp	non-coding		165 bp	315 bp	1	marrow

Function

As mentioned previously, the specific function and however, its function can be largely inferred through the study of similar genes. DOP1B has been found to be involved in the following processes: multicellular organism development in cell differentiation and developmental patterning, cognition, as well as endoplasmic reticulum organization and Golgi to endosome transport.

Cell differentiation and patterning

The DOP1B ortholog, pad-1, in C. elegans, was found to have a role in cell differentiation and patterning. In an experiment where the pad-1 was silenced using RNA-mediated interference, the phenotype of the injected worm's offspring was fetal lethality. The reason being: most of the embryonic tissues did not undergo appropriate cell patterning during gastrulation. Abnormally positioned cells lead to misinformation of organs; the failed morphogenesis of embryo. A similar observation was made in the inactivation of the Dop1 gene, the DOP1B ortholog, in S. cerevisiae. The inactivation lead to abnormal cell positioning and subsequent death. Overexpression of the N-terminal in S. cerevisiae also resulted in a loss of proper growth polarity and abnormal asexual reproductive patterning. This function was further supported by the function of the ortholog DopA in A. nidulans, which similarly codes for a 207kDa protein that also contains leucine zipper-like domains. Its inactivation revealed its role directing alternations in cell division timing, growth polarity, as well as cell-specific gene expression, ultimately affecting organogenesis and cell differentiation.

Endoplasmic reticulum and golgi transport

Dop1, an ortholog of DOP1B, in S. cerevisiae was found to play an essential role in membrane organization. It was found that it forms a complex with another protein, Mon2, which recruits the pool of Dop1 from the Golgi. In a Mon2 knockout model, Dop1 was mislocalized, and in turn resulted in defective cycling between endosomes and the Golgi. In a Dop1 knockout model, severe defects in the endoplasmic reticulum organization. This Dop1 and Mon2 complex was also linked to traffic in the endocytic pathway.

Clinical significance

Cognition

DOP1B has been identified as a CNV region in Alzheimer's disease subjects, and its triplication has been tied to various phenotypic aspects of Down Syndrome.

Down syndrome

DOP1B has been associated with the Down Syndrome phenotype. When DOP1B was overexpressed in mice, abnormal lamination patterns of cortical cells was observed, as well as altered cortical, hippocampal, and cerebellar cells, regions that play key roles in memory and learning. These changes are similar to those observed in Down Syndrome patients. It is because of this that C21orf15 is now being studied as a new candidate gene for the intellectual disability phenotype in Down Syndrome.

See also

• Down Syndrome
• Chromosome 21

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (June 2002). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Research. 9 (3): 99–106. CiteSeerX 10.1.1.500.923. doi:10.1093/dnares/9.3.99. PMID 12168954.
• Dahmane N, Ghezala GA, Gosset P, Chamoun Z, Dufresne-Zacharia MC, Lopes C, Rabatel N, Gassanova-Maugenre S, Chettouh Z, Abramowski V, Fayet E, Yaspo ML, Korn B, Blouin JL, Lehrach H, Poutska A, Antonarakis SE, Sinet PM, Créau N, Delabar JM (February 1998). "Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome". Genomics. 48 (1): 12–23. doi:10.1006/geno.1997.5146. PMID 9503011.
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (February 1999). "Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 6 (1): 63–70. doi:10.1093/dnares/6.1.63. PMID 10231032.
• Guipponi M, Brunschwig K, Chamoun Z, Scott HS, Shibuya K, Kudoh J, Delezoide AL, El Samadi S, Chettouh Z, Rossier C, Shimizu N, Mueller F, Delabar JM, Antonarakis SE (August 2000). "C21orf5, a novel human chromosome 21 gene, has a Caenorhabditis elegans ortholog (pad-1) required for embryonic patterning". Genomics. 68 (1): 30–40. doi:10.1006/geno.2000.6250. PMID 10950924.
• Lopes C, Chettouh Z, Delabar JM, Rachidi M (June 2003). "The differentially expressed C21orf5 gene in the medial temporal-lobe system could play a role in mental retardation in Down syndrome and transgenic mice". Biochemical and Biophysical Research Communications. 305 (4): 915–24. doi:10.1016/S0006-291X(03)00867-2. PMID 12767918.
• Rachidi M, Lopes C, Delezoide AL, Delabar JM (2006). "C21orf5, a human candidate gene for brain abnormalities and mental retardation in Down syndrome". Cytogenetic and Genome Research. 112 (1–2): 16–22. doi:10.1159/000087509. PMID 16276086. S2CID 22696699.