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.

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.

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 VariantSpliced mRNA LengthProtein Length5' UTR3' UTRUnspliced pre-mRNA LengthNumber of ExonsTissue-mRNA Expression (no strict specificity implied)aAug107691 bp2298 aa85 bp709 bp129746 bp37ubiquitousbAug102173 bp332aa1174 bp15610 bp6carcinoid, lung, colon, colon tumor, RER+cAug10742 bp222 aa74 bp49789 bp6breast, t-lymphocytesdAug10623 bp145 aa188 bp43664 bp4lungeAug10345 bp114 aa9925 bp3spleenfAug10571 bp110 aa241 bp1322 bp2thalamusgAug10549 bpnon-coding11 bp499 bp794 bp2spleenhAug- unspliced543 bpnon-coding377 bp543 bp1stomachiAug10514 bpnon-coding205 bp204 bp7377 bp2thyroid glandjAug10- unspliced315 bpnon-coding165 bp315 bp1marrow

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 patients with Down syndrome. It is because of this that C21orf15 is now being studied as a new candidate gene for the intellectual disability phenotype in Down Syndrome.

DOP1B

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