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Background

My name is Justine Nowicki, I am a student in BIO3595 (Advanced Genetics) at Western University. I am an undergraduate student pursuing a Ivey HBA (Honours Business Administration) and Honours Specialization in Genetics.

DOPEY2

DOPEY2 is a human gene located just above the Down Syndrome chromosomal region (DSCR) located at 21p22.2 sub-band. Although the exact function of the 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 DOPEY2 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. DOPEY2 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 the table below:

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

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 10 mRNAs produced, 6 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, DOPEY2.a, is composed of 2298 amino acids that make up an N-terminal domain, 7 transmembrane domains, and a C-terminal coiled coil stretch that forms a leucine-like zipper domain. Like other leucine zippers domains, DOPEY2's C-terminal is hypothesized to be involved in multiple protein-protein and transcription factor interactions. This indicates that DOPEY2 might act as a transcription co-activator; however, further research must be done to fully understand the precise physiological function.

Protein Interactions

Although 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. DOPEY2 is also indirectly associated with the following proteins: ARL16, ATP9A, ARL1, ATP9B, UBE3A, HERC5, HERC4, HACE1, UBE3C, and UBR5.

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 DOPEY2 can be traced back to a common ancestor of animals and fungi due to its highly conserved C-terminal domain DOPEY2 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 DOPEY2 protein to 5 main areas: the Golgi membrane, endosomes, 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.

Function

AS mentioned previously, the specific function and however, its function can be largely inferred through the study of similar genes. DOPEY2 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 DOPEY2 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, as 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 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.

Cognition

DOPEY2 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.

Endoplasmic Reticulum and Golgi Transport

Dop1, an ortholog of DOPEY2, in S. cerevisiae was found to play a 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 enocytic pathway.

Clinical Relevance

DOPEY2 has been linked to the Down Syndrome phenotype. When DOPEY2 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 mental retardation phenotype in Down Syndrome.