DDOST-CDG

What is DDOST?

DDOST is the name of gene that encodes an enzyme called dolichyl-diphosphooligosaccharide-protein glycosyltransferase. DDOST is the beta subunit of the oligosaccharyltransferase (OST) complex. It has the distinction of being evolutionarily conserved in the endoplasmic reticulum of every cell of every animal in the animal kingdom.

The OST complex contains DDOST and eight possible subunits: RPN1, RPN2, DDOST, DAD1, STT3A or STT3B, TUSC3 or MAGT1, and OST4. Like other complex molecular machines engaged in rapid transport processes and parallel biosynthetic reactions inside the cell, the individual OST complex subunits row in unison within the endoplasmic reticulum, each subunit in its irreplaceable position, together enabling the final step of N-linked glycosylation. The transfer of the oligosaccharide from the lipid carrier dolichyl-diphosphooligosaccharide to asparagine attachment sites in just born proteins.

Figure 1A reproduced from Bai et al., 2018 showing the yeast OST complex at atomic resolution from back and front views.

Mutations in DDOST result in OST complex instability, but the biochemical details remain to be elucidated. In relation to the other CDG-1 genes, the OST complex acts directly on lipid-linked oligosaccharide, or LLO, which is downstream of dolichol biosynthesis genes like SRD5A3 and DOLK. Mutations in all subunits of the OST complex except OST4 and RPN1 result in a congenital disorder of glycosylation, as described in the following clinical reports:

There’s only one published report of a DDOST-CDG diagnosis followed clinical whole exome sequencing: Jones et al., 2012. DDOST-CDG patient fibroblasts were shown to exhibit hypoglycosylation phenotypes shared by fibroblasts from other CDG-1 patients, including reduction in the amount of secreted DNase I and loss of ICAM-1 expression. The authors performed an important control experiment. Expression of DDOST in DDOST-CDG fibroblasts was sufficient to rescue hypoglycosylation phenotypes.

I can’t help but sense a missed opportunity to replicate the disease modeling recipe finetuned by Cantagrel et al., 2010 for SRD5A3-CDG yeast models. The playbook has already been successfully replicated for PMM2-CDG yeast models (Lao et al., 2019).

Next steps for DDOST-CDG 

The DDOST-CDG community needs to grow vertically by identifying new DDOST-CDG patients but also horizontally by joining forces with allied OST complex CDG disease communities. 

Another way to expand the DDOST-CDG community is to search among undiagnosed patients with clinical features similar to DDOST-CDG, as noted by Jones et al: “Given that mutations within the OST complex result in a fairly mild phenotype and can result in intellectual disability, this gene might be of interest in patients with intellectual disability.”
The DDOST-CDG community will eventually hit a critical mass. Fundraising, a natural history study, and a multi-year research plan will naturally follow. The first research investments should go toward generating a suite of DDOST-CDG disease models spanning yeast, worms, flies, zebrafish, and mice.

The orthologs, or ancestral versions, of DDOST across plants, fungi and animals.

Patient fibroblasts have already been validated by Jones et al, and the next logical step is to generate iPSCs. The two purposes for having a diverse portfolio of disease models is (1) to identify phenotypes amenable to high-throughput drug screening and (2) biomarker discovery to enable robust clinical trials. 

References

Bai L, Wang T, Zhao G, Kovach A, Li H. (2018). The atomic structure of a eukaryotic oligosaccharyltransferase complex. Nature. 555: 328-333. 

Blommaert E, Péanne R, Cherepanova NA, Rymen D, Staels F, Jaeken J, Race V, Keldermans L, Souche E, Corveleyn A, Sparkes R, Bhattacharya K, Devalck C, Schrijvers R, Foulquier F, Gilmore R, Matthijs G. (2019). Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype. Proceedings of the National Academy of Sciences. 116: 9865-9870.

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Blümel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. (2010). SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 142: 203-217.

El Chehadeh S, Bonnet C, Callier P, Béri M, Dupré T, Payet M, Ragon C, Mosca-Boidron AL, Marle N, Mugneret F, Masurel-Paulet A, Thevenon J, Seta N, Duplomb L, Jonveaux P, Faivre L, Thauvin-Robinet C. (2015). Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers. JIMD Rep. 20: 45-55.

Jones MA, Ng BG, Bhide S, Chin E, Rhodenizer D, He P, Losfeld ME, He M, Raymond K, Berry G, Freeze HH, Hegde MR. (2012). DDOST Mutations Identified by Whole-Exome Sequencing Are Implicated in Congenital Disorders of Glycosylation. American Journal of Human Genetics. 90: 363-368.

Lao JP, DiPrimio N, Prangley M, Sam FS, Mast JD, Perlstein EO. (2019). Yeast Models of Phosphomannomutase 2 Deficiency, a Congenital Disorder of Glycosylation. G3. 9: 413-423.

Shrimal S, Ng BG, Losfeld ME, Gilmore R, Freeze HH. (2012). Mutations in STT3A and STT3B cause two congenital disorders of glycosylation. Human Molecular Genetics. 22: 4638-4645.
Vleugels W, Schollen E, Foulquier F, Matthijs G. (2009). Screening for OST deficiencies in unsolved CDG-I patients.Biochemical and Biophysical Research Communications. 390: 769-74.

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