Alternative titles; symbols
HGNC Approved Gene Symbol: MOGS
SNOMEDCT: 725028009;
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38): 2:74,461,057-74,465,382 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.1 | Congenital disorder of glycosylation, type IIb | 606056 | Autosomal recessive | 3 |
The processing of N-linked glycoproteins is initiated by the action of glucosidase I, which cleaves specifically the distal alpha-1,2-linked glucose residue in the Glc(3)-Man(9)-GlcNAc(2) oligosaccharide precursor after its en bloc transfer from dolichyl diphosphate to the nascent polypeptide chain (Kornfeld and Kornfeld, 1985). The resulting Glc(2)-Man(9)-GlcNAc(2) intermediate is then further modified by glucosidase II and several ER- and Golgi-resident mannosidases and glycosyltransferases, finally yielding a complex array of glycan structures.
Kalz-Fuller et al. (1995) used the amino acid sequence of tryptic peptides of the pig liver glucosidase I enzyme to synthesize degenerate oligonucleotides that were used to amplify a specific cDNA probe by PCR with porcine cDNA. Screening of a human hippocampus cDNA library with this probe resulted in the isolation of several glucosidase I-specific clones, allowing the reconstruction of a full-length human cDNA of 2,881 bp. The oligonucleotide sequence showed no homology to other processing enzymes cloned to that time.
By fluorescence in situ hybridization, Kalz-Fuller et al. (1996) mapped the GCS1 gene to chromosome 2p13-p12. They confirmed the localization with PCR-based analysis of somatic cell hybrids.
De Praeter et al. (2000) identified a glucosidase I defect in a neonate with severe generalized hypotonia and dysmorphic features consistent with congenital disorder of glycosylation type IIb (CDG2B; 606056). Molecular studies showed that the patient was a compound heterozygote for 2 missense mutations in the GCS1 gene (601336.0001-601336.0002).
In 2 sibs with CDG2B, Sadat et al. (2014) identified compound heterozygous mutations in the MOGS gene (601336.0003 and 601336.0004). The mutations resulted in lack of detectable protein expression. Each unaffected parent was heterozygous for 1 of the mutant alleles.
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 MOGS is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a neonate with congenital disorder of glycosylation type IIb (CDG2B; 606056), De Praeter et al. (2000) identified compound heterozygosity for 2 missense mutations in the GCS1 gene: a 1587G-C transition resulting in an arg486-to-thr (R486T) substitution, and a 2085T-C transition resulting in a phe652-to-leu (F652L; 601336.0002) substitution. The mother was heterozygous for the former mutation, whereas the father was heterozygous for the latter. The patient was the first child of second-cousin parents and presented with severe generalized hypotonia and dysmorphic features.
For discussion of the phe652-to-leu (F652L) mutation found in compound heterozygous state in a patient with congenital disorder of glycosylation type IIb (CDG2B; 606056) by De Praeter et al. (2000), see 601336.0001.
In 2 sibs with congenital disorder of glycosylation type IIb (CDG2B; 606056), Sadat et al. (2014) identified compound heterozygous mutations in the MOGS gene. The maternal allele carried a c.370C-T transition, predicted to result in a gln124-to-ter (Q124X) substitution; the mutation resulted in nonsense-mediated mRNA decay. The paternal allele had 2 mutations: a c.65C-A transversion, predicted to result in an ala22-to-glu (A22E) substitution, and a c.329G-A transition, predicted to result in an arg110-to-his (R110H) substitution (601336.0004). The c.65C-A mutation affected splicing and resulted in nonsense-mediated mRNA decay, and the R110H mutant protein was rapidly degraded by the proteasome. Immunoblot analysis of patient cells showed lack of detectable MOGS protein, consistent with a loss of function. The patients had global developmental delay, hypotonia, seizures, dysmorphic features, and hypogammaglobulinemia.
Kane et al. (2016) found that fibroblasts and blood derived from the sibs reported by Sadat et al. (2014) had increased amounts of nonparental genotypes surrounding the inherited variants. Detailed analysis indicated that there were some somatic genotypes with the wildtype allele. These findings suggested that reciprocal mitotic recombination can generate wildtype alleles in somatic cells, which may contribute to the survival and the variable expressivity seen in individuals with compound heterozygous mutations.
For discussion of the ala22-to-glu (A22E) and arg110-to-his (R110H) mutations found in cis on the paternal allele in compound heterozygous state in a patient with congenital disorder of glycosylation type IIb (CDG2B; 606056) by Sadat et al. (2014), see 601336.0003.
De Praeter, C. M., Gerwig, G. J., Bause, E., Nuytinck, L. K., Vliegenthart, J. F. G., Breuer, W., Kamerling, J. P., Espeel, M. F., Martin, J.-J. R., De Paepe, A. M., Chan, N. W. C., Dacremont, G. A., Van Coster, R. N. A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. Am. J. Hum. Genet. 66: 1744-1756, 2000. [PubMed: 10788335] [Full Text: https://doi.org/10.1086/302948]
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]
Kalz-Fuller, B., Bieberich, E., Bause, E. Cloning and expression of glucosidase I from human hippocampus. Europ. J. Biochem. 231: 344-351, 1995. Note: Erratum: Europ. J. Biochem. 249: 912 only, 1997. [PubMed: 7635146] [Full Text: https://doi.org/10.1111/j.1432-1033.1995.tb20706.x]
Kalz-Fuller, B., Heidrich-Kaul, C., Nothen, M., Bause, E., Schwanitz, G. Localization of the human glucosidase I gene to chromosome 2p12-p13 by fluorescence in situ hybridization and PCR analysis of somatic cell hybrids. Genomics 34: 442-443, 1996. [PubMed: 8786151] [Full Text: https://doi.org/10.1006/geno.1996.0313]
Kane, M. S., Davids, M., Adams, C., Wolfe, L. A., Cheung, H. W., Gropman, A., Huang, Y., NISC Comparative Sequencing Program, Ng, B. G., Freeze, H. H., Adams, D. R., Gahl, W. A., Boerkoel, C. F. Mitotic intragenic recombination: a mechanism of survival for several congenital disorders of glycosylation. Am. J. Hum. Genet. 98: 339-346, 2016. [PubMed: 26805780] [Full Text: https://doi.org/10.1016/j.ajhg.2015.12.007]
Kornfeld, R., Kornfeld, S. Assembly of asparagine-linked oligosaccharides. Annu. Rev. Biochem. 54: 631-664, 1985. [PubMed: 3896128] [Full Text: https://doi.org/10.1146/annurev.bi.54.070185.003215]
Sadat, M. A., Moir, S., Chun, T.-W., Lusso, P., Kaplan, G., Wolfe, L., Memoli, M. J., He, M., Vega, H., Kim, L. J. Y., Huang, Y., Hussein, N., and 28 others. Glycosylation, hypogammaglobulinemia, and resistance to viral infections. New. Eng. J. Med. 370: 1615-1625, 2014. [PubMed: 24716661] [Full Text: https://doi.org/10.1056/NEJMoa1302846]