Alternative titles; symbols
HGNC Approved Gene Symbol: DDOST
SNOMEDCT: 733083006;
Cytogenetic location: 1p36.12 Genomic coordinates (GRCh38): 1:20,651,777-20,661,369 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.12 | Congenital disorder of glycosylation, type Ir | 614507 | Autosomal recessive | 3 |
The DDOST gene encodes the enzyme oligosaccharyltransferase (dolichyl-diphosphooligosaccharide-protein glycosyltransferase (EC 2.4.1.119)), which catalyzes the transfer of a high-mannose oligosaccharide from a dolichyl-linked oligosaccharide donor onto the asparagine acceptor site in nascent polypeptide chains across the membrane of the rough endoplasmic reticulum (Yamagata et al., 1997).
Kelleher et al. (1992) reported that mammalian oligosaccharyltransferase activity is associated with a protein complex composed of ribophorin I (180470), ribophorin II (180490), and a 48-kD protein, OST48.
Yamagata et al. (1997) isolated mouse and human DDOST cDNAs from retinoic acid-treated mouse and human cells. DDOST mRNA was expressed intensely in heart and pancreas, but at lower levels in brain.
Yamagata et al. (1997) showed that the gene encoding the human DDOST 48-kD gene is organized into 11 exons spanning about 9 kb.
By fluorescence in situ hybridization, Yamagata et al. (1997) assigned the DDOST gene to chromosome 1p36.1.
Advanced glycosylation end products (AGE) contribute to kidney disease due to diabetes or aging by means of mesangial cell receptors, such as receptor for AGE (RAGE; 600214), which promote oxidant stress-dependent activation of NF-kappa-B (see 164011) and inflammatory gene expression. Lu et al. (2004) found that DDOST, which they referred to as AGE receptor-1 (AGE-R1), enhances AGE removal, but is also a distinct receptor in that it suppresses AGE-mediated mesangial cell inflammatory injury through negative regulation of RAGE, a previously uncharacterized pathway that may protect from renal and other tissue injury due to diabetes and aging.
Using a gene trap-based system to create knockin mouse embryonic stem cells, followed by tandem affinity purification, MacLeod and Varmuza (2012) identified significant protein-protein interactions of Ppp1cc (176914) with 9 Pp1-interacting proteins and 2 additional proteins, Ddost and Atp5c1 (108729). Sedimentation and Western blot analyses confirmed interaction of the testis-specific Ppp1cc2 isoform with Ddost. Confocal microscopy demonstrated localization of Ddost at the nuclear envelope in mouse spermatogenic cells.
By whole-exome sequencing of a European boy with congenital disorder of glycosylation type 1r (CDG1R; 614507), Jones et al. (2012) identified compound heterozygosity for 2 mutations in the DDOST gene (602202.0001 and 602202.0002). The patient presented in infancy with failure to thrive, gastroesophageal reflux, developmental delay, and oromotor dysfunction. He later showed hypotonia, external strabismus, and mild to moderate liver dysfunction. He had delayed psychomotor development with walking acquired at age 3 years, and never developed speech.
In a patient with CDG1R, Pi et al. (2022) identified a homozygous missense mutation in the DDOST gene (R396Q; 602202.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Serum transferrin isoelectric focusing showed a type 1 pattern.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human DDOST is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
By whole-exome sequencing of a European boy with congenital disorder of glycosylation type Ir (CDG1R; 614507), Jones et al. (2012) identified compound heterozygosity for 2 mutations in the DDOST gene: a 22-bp deletion in exon 11 (c.1265_1286del22), resulting in a frameshift, truncation of 29 C-terminal residues, and a presumably nonfunctional protein, and a c.650G-A transition in exon 6, resulting in a gly217-to-asp (G217D; 602202.0002) substitution at a highly conserved residue in the luminal domain of the endoplasmic reticulum. Neither mutation was found in the 1000 Genomes Project database or in 100 controls, and each unaffected parent was heterozygous for one of the mutations. Immunoblot analysis of patient fibroblasts showed a 50% reduction in DDOST protein expression. Several biochemical studies showed that the patient's fibroblasts had an N-glycosylation defect, which could be corrected by transfection with wildtype DDOST. The patient presented in infancy with failure to thrive, gastroesophageal reflux, developmental delay, and oromotor dysfunction. He later showed hypotonia, external strabismus, and mild to moderate liver dysfunction. He had delayed psychomotor development with walking acquired at age 3 years, and never developed speech.
For discussion of the gly217-to-asp (G217D) mutation in the DDOST gene that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type Ir (CDG1R; 614507) by Jones et al. (2012), see 602202.0001.
In a Chinese boy, born to consanguineous parents, with congenital disorder of glycosylation type Ir (CDG1R; 614507), Pi et al. (2022) identified a homozygous c.1187G-A transition (c.1187G-A, NM_005216.4) in exon 10 of the DDOST gene, resulting in an arg396-to-gln (R396Q) substitution at a conserved residue. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The frequency of the R396Q mutation was 0.0001 in both the gnomAD and ExAC databases. Transferrin isoelectric focusing in patient serum showed a type 1 pattern.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Jones, M. A., Ng, B. G., Bhide, S., Chin, E., Rhodenizer, D., He, P., Losfeld, M.-E., He, M., Raymond, K., Berry, G., Freeze, H. H., Hegde, M. R. DDOST mutations identified by whole-exome sequencing are implicated in congenital disorders of glycosylation. Am. J. Hum. Genet. 90: 363-368, 2012. [PubMed: 22305527] [Full Text: https://doi.org/10.1016/j.ajhg.2011.12.024]
Kelleher, D. J., Kreibich, G., Gilmore, R. Oligosaccharyltransferase activity is associated with a protein complex composed of ribophorins I and II and a 48 kd protein. Cell 69: 55-65, 1992. [PubMed: 1555242] [Full Text: https://doi.org/10.1016/0092-8674(92)90118-v]
Lu, C., He, J. C., Cai, W., Liu, H., Zhu, L., Vlassara, H. Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells. Proc. Nat. Acad. Sci. 101: 11767-11772, 2004. [PubMed: 15289604] [Full Text: https://doi.org/10.1073/pnas.0401588101]
MacLeod, G., Varmuza, S. Tandem affinity purification in transgenic mouse embryonic stem cells identifies DDOST as a novel PPP1CC2 interacting protein. Biochemistry 51: 9678-9688, 2012. [PubMed: 23140390] [Full Text: https://doi.org/10.1021/bi3010158]
Pi, S., Gong, J., Xiao, W., Xiao, B., Mao, X., Long, H. The second DDOST-CDG patient with lactose intolerance, developmental delay, and situs inversus totalis. J. Hum. Genet. 67: 103-106, 2022. [PubMed: 34462534] [Full Text: https://doi.org/10.1038/s10038-021-00974-2]
Yamagata, T., Tsuru, T., Momoi, M. Y., Suwa, K., Nozaki, Y., Mukasa, T., Ohashi, H., Fukushima, Y., Momoi, T. Genome organization of human 48-kDa oligosaccharyltransferase (DDOST). Genomics 45: 535-540, 1997. [PubMed: 9367678] [Full Text: https://doi.org/10.1006/geno.1997.4966]