Mannosyl-oligosaccharide Glucosidase Research Articles

Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature.

Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG.

Targeting Leishmania infantum Mannosyl-oligosaccharide glucosidase with natural products: potential pH-dependent inhibition explored through computer-aided drug design.

Visceral Leishmaniasis (VL) is a serious public health issue, documented in more than ninety countries, where an estimated 500,000 new cases emerge each year. Regardless of novel methodologies, advancements, and experimental interventions, therapeutic limitations, and drug resistance are still challenging. For this reason, based on previous research, we screened natural products (NP) from Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBEDB), Mexican Compound Database of Natural Products (BIOFACQUIM), and Peruvian Natural Products Database (PeruNPDB) databases, in addition to structural analogs of Miglitol and Acarbose, which have been suggested as treatments for VL and have shown encouraging action against parasite's N-glycan biosynthesis. Using computer-aided drug design (CADD) approaches, the potential inhibitory effect of these NP candidates was evaluated by inhibiting the Mannosyl-oligosaccharide Glucosidase Protein (MOGS) from Leishmania infantum, an enzyme essential for the protein glycosylation process, at various pH to mimic the parasite's changing environment. Also, computational analysis was used to evaluate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profile, while molecular dynamic simulations were used to gather information on the interactions between these ligands and the protein target. Our findings indicated that Ocotillone and Subsessiline have potential antileishmanial effects at pH 5 and 7, respectively, due to their high binding affinity to MOGS and interactions in the active center. Furthermore, these compounds were non-toxic and had the potential to be administered orally. This research indicates the promising anti-leishmanial activity of Ocotillone and Subsessiline, suggesting further validation through in vitro and in vivo experiments.

Strategic self-limiting production of infectious HIV particles by CRISPR in permissive cells

Post-translational glycosylation of the HIV-1 envelope protein involving precursor glycan trimming by mannosyl oligosaccharide glucosidase (MOGS) is critically important for morphogenesis of virions and viral entry. Strategic editing of the MOGS gene in T lymphocytes and myeloid origin cells harboring latent proviral DNA results in the production of non-infectious particles upon treatment of cells with latency reversal agents. Controlled activation of CRISPR-MOGS by rebound HIV-1 mitigates production of infectious particles that exhibit poor ability of the virus to penetrate uninfected cells. Moreover, exclusive activation of CRISPR in cells infected with HIV-1 alleviates concern for broad off-target impact of MOGS gene ablation in uninfected cells. Combination CRISPR treatment of peripheral blood lymphocytes prepared from blood of people with HIV-1 (PWH) tailored for editing the MOGS gene (CRISPR-MOGS) and proviral HIV-1 DNA (CRISPR-HIV) revealed a cooperative impact of CRISPR treatment in inhibiting the production of infectious HIV-1 particles. Our design for genetic inactivation of MOGS by CRISPR exhibits no detectable off-target effects on host cells or any deleterious impact on cell survival and proliferation. Our findings offer the development of a new combined gene editing-based cure strategy for the diminution of HIV-1 spread after cessation of antiretroviral therapy (ART) and its elimination.

Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports

BACKGROUNDMannosyl-oligosaccharide glucosidase (MOGS) deficiency is an extremely rare type of congenital disorder of glycosylation (CDG), with only 12 reported cases. Its clinical, genetic, and glycomic features are still expanding. Our aim is to update the novel clinical and glycosylation features of 2 previously reported patients with MOGS-CDG.CASE SUMMARYWe collected comprehensive clinical information, and conducted the immunoglobulin G1 glycosylation assay using nano-electrospray ionization source quadruple time-of-flight mass spectrometry. Novel dysmorphic features included an enlarged tongue, forwardly rotated earlobes, a birth mark, overlapped toes, and abnormal fat distribution. Novel imaging findings included pericardial effusion, a deep interarytenoid groove, mild congenital subglottic stenosis, and laryngomalacia. Novel laboratory findings included peripheral leukocytosis with neutrophil predominance, elevated C-reactive protein and creatine kinase, dyslipidemia, coagulopathy, complement 3 and complement 4 deficiencies, decreased proportions of T lymphocytes and natural killer cells, and increased serum interleukin 6. Glycosylation studies showed a significant increase of hypermannosylated glycopeptides (Glc3Man7GlcNAc2/N2H10 and Man5GlcNAc2/N2H5) and hypersialylated glycopeptides. A compensatory glycosylation pathway leading to an increase in Man5GlcNAc2/N2H5 was indicated with the glycosylation profile. CONCLUSIONWe confirmed abnormal glycomics in 1 patient, expanding the clinical and glycomic spectrum of MOGS-CDG. We also postulated a compensatory glycosylation pathway, leading to a possible serum biomarker for future diagnosis.

Metabolism-related MOGS Gene is Dysregulated After Peripheral Nerve Injury and Negatively Regulates Schwann Cell Plasticity

Cellular metabolism is essentially linked to tissue remodeling and organ regeneration. MOGS, a gene that encodes cellular metabolism-related protein mannosyl-oligosaccharide glucosidase, was found to be upregulated in nerve segments after peripheral nerve injury. Bioinformatic analyses identified upstream regulators of MOGS and MOGS-associated genes and indicated the significant involvement of cellular metabolism in peripheral nerve regeneration. Functional assessment showed that siRNA-mediated knockdown of MOGS led to elevated proliferation, migration, and differentiation of Schwann cells, indicating the negative regulation of MOGS on Schwann cell plasticity. Schwann cells transfected with MOGS siRNA also showed lower expression of fatty acid synthase (FASN), demonstrating that dysregulated MOGS in Schwann cells may affect neuronal behavior through the metabolic coupling between Schwann cells and axons. Taken together, this study demonstrated that MOGS may be a key regulating factor of Schwann cells and neuronal phenotype during peripheral nerve regeneration.

N-Glycan Modification in Covid-19 Pathophysiology: In vitro Structural Changes with Limited Functional Effects.

In 2014, we reported two siblings with a rare congenital disorder of glycosylation due to mutations in mannosyl-oligosaccharide glucosidase (MOGS). The glycan alteration derived from this disease resulted in an in vitro infection resistance to particular enveloped, N-glycosylation-dependent viruses as influenza and HIV. As part of the global effort to find safe and effective antiviral therapies for Covid-19, we assessed the in vitro activity of the FDA-approved α-glucosidase inhibitor miglustat against SARS-CoV-2. Expression plasmids encoding SARS-CoV-2 spike (S) and human ACE2 glycoproteins (GP) were tested to evaluate N-glycan modifications induced by α-glucosidase inhibition. Immunoprecipitation was used to assess binding between these two GP. Cell-to-cell fusion was assessed by immunofluorescence of cocultures of SARS-CoV-2 S and ACE2-expressing cells. Miglustat effect on immune response was tested by measuring cytokine release from PBMC exposed to purified SARS-CoV-2 S. In our overexpression system, miglustat successfully and specifically modified N-glycans in both SARS-CoV-2 S and its main receptor ACE2. Binding between these two GP was not affected by glycan modifications. A surrogate marker for viral cytopathic effect, measured as receptor-dependent SARS-CoV-2 S-driven cell-to-cell fusion, was not disrupted by miglustat treatment. This observation was further confirmed in MOGS-null transfected cells. Miglustat produced no statistically significant effects on cytokine production following SARS-CoV-2 S glycoprotein stimulation of PBMC. Our work shows that despite clear N-glycan alteration in the presence of miglustat, the functions of the Covid-19-related glycoproteins studied were not affected, making it unlikely that miglustat can change the natural course of the disease.

Identification and characterization of novel mutations in MOGS in a Chinese patient with infantile spams.

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of disorders caused by the defects in the synthesis and processing of glycoproteins. CDG is caused by mannosyl-oligosaccharide glucosidase (MOGS) deficiency, and is an extremely rare type, and only six patients have been reported. Here, we report a patient from China with facial dysmorphism, infantile spams, developmental delay, low vison, and abnormal liver function and low immunoglobulin. Brain MRI showed hypoplasia of the corpus callosum and slightly wide sulci at bilateral frontal parietal lobes. Compound heterozygous mutations of (c.1694G>A: R565Q and c.1619G>A: R540H) in exon 4 of MOGS gene (NM_006302.2) were identified by whole exome sequencing. Further investigation showed that the gene expression of MOGS in patients' peripheral blood was decreased. We observed that two mutations were associated with lower protein expression of MOGS, cell growth, and cell cycle in transiently transfected Hela cells. We also noticed that cell cycle-related proteins, β-catenin, cyclin D1, and C-myc, were decreased in mutant cells. In conclusion, our study suggested whole exome sequencing, and genes associated with CDGs should be analyzed in patients with infantile spams and multiple system involvement, and mutant MOGS-impaired cell cycle progression. Our work broadens the mutation spectrum of MOGS gene.

P32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression.

Sustained endoplasmic reticulum (ER) stress plays a major role in the development of many metabolic diseases, including cardiovascular disease, nonalcoholic fatty liver disease, insulin resistance, obesity, and diabetes. p32 is a multicompartmental protein involved in the regulation of oxidative phosphorylation and glucose oxidation. p32 ablation is associated with resistance to age-associated and diet-induced obesity through a mechanism that remains largely unknown. Here, we show that p32 promotes lipid biosynthesis by modulating fatty acid-induced ER stress. We found that p32 interacts with endoplasmic reticulum-anchored enzyme mannosyl-oligosaccharide glucosidase I (GCS1), an ER lumen-anchored glucosidase that is essential for the processing of N-linked glycoproteins, and reduces GCS1 in a lysosome-dependent manner. We demonstrate that increased GCS1 expression alleviates fatty acid-induced ER stress and is critical for suppressing ER stress-associated lipogenic gene activation, as demonstrated by the down-regulation of Srebp1, Fasn, and Acc. Consistently, suppression of p32 leads to increased GCS1 expression and alleviates fatty acid-induced ER stress, resulting in reduced lipid accumulation. Thus, p32 and GCS1 are regulators of ER function and lipid homeostasis and are potential therapeutic targets for the treatment of obesity and diabetes.-Liu, Y., Leslie, P. L., Jin, A., Itahana, K., Graves, L. M., Zhang, Y. p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression.

Detection of phosphoglucomutase-3 deficiency by lectin-based flow cytometry

Detection of phosphoglucomutase-3 deficiency by lectin-based flow cytometry

Mitotic Intragenic Recombination: A Mechanism of Survival for Several Congenital Disorders of Glycosylation

Congenital disorders of glycosylation (CDGs) are disorders of abnormal protein glycosylation that affect multiple organ systems. Because most CDGs have been described in only a few individuals, our understanding of the associated phenotypes and the mechanisms of individual survival are limited. In the process of studying two siblings, aged 6 and 11 years, with MOGS-CDG and biallelic MOGS (mannosyl-oligosaccharide glucosidase) mutations (GenBank: NM_006302.2; c.[65C>A; 329G>A] p.[Ala22Glu; Arg110His]; c.[370C>T] p.[Gln124(∗)]), we noted that their survival was much longer than the previous report of MOGS-CDG, in a child who died at 74days of age. Upon mutation analysis, we detected multiple MOGS genotypes including wild-type alleles in their cultured fibroblast and peripheral blood DNA. Further analysis of DNA from cultured fibroblasts of six individuals with compound heterozygous mutations of PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also identified multiple genotypes including wild-type alleles for each. Droplet digital PCR showed a ratio of nearly 1:1 wild-type to mutant alleles for most, but not all, mutations. This suggests that mitotic recombination contributes to the survival and the variable expressivity of individuals with compound heterozygous CDGs. This also provides an explanation for prior observations of a reduced frequency of homozygous mutations and might contribute to increased levels of residual enzyme activity in cultured fibroblasts of individuals with MPI- and PMM2-CDGs.

Glycosylation, Hypogammaglobulinemia, and Resistance to Viral Infections

Genetic defects in MOGS, the gene encoding mannosyl-oligosaccharide glucosidase (the first enzyme in the processing pathway of N-linked oligosaccharide), cause the rare congenital disorder of glycosylation type IIb (CDG-IIb), also known as MOGS-CDG. MOGS is expressed in the endoplasmic reticulum and is involved in the trimming of N-glycans. We evaluated two siblings with CDG-IIb who presented with multiple neurologic complications and a paradoxical immunologic phenotype characterized by severe hypogammaglobulinemia but limited clinical evidence of an infectious diathesis. A shortened immunoglobulin half-life was determined to be the mechanism underlying the hypogammaglobulinemia. Impaired viral replication and cellular entry may explain a decreased susceptibility to infections.

OsMOGS is required for N‐glycan formation and auxin‐mediated root development in rice (Oryza sativa L.)

N-glycosylation is a major modification of glycoproteins in eukaryotic cells. In Arabidopsis, great progress has been made in functional analysis of N-glycan production, however there are few studies in monocotyledons. Here, we characterized a rice (Oryza sativa L.) osmogs mutant with shortened roots and isolated a gene that coded a putative mannosyl-oligosaccharide glucosidase (OsMOGS), an ortholog of α-glucosidase I in Arabidopsis, which trims the terminal glucosyl residue of the oligosaccharide chain of nascent peptides in the endoplasmic reticulum (ER). OsMOGS is strongly expressed in rapidly cell-dividing tissues and OsMOGS protein is localized in the ER. Mutation of OsMOGS entirely blocked N-glycan maturation and inhibited high-mannose N-glycan formation. The osmogs mutant exhibited severe defects in root cell division and elongation, resulting in a short-root phenotype. In addition, osmogs plants had impaired root hair formation and elongation, and reduced root epidemic cell wall thickness due to decreased cellulose synthesis. Further analysis showed that auxin content and polar transport in osmogs roots were reduced due to incomplete N-glycosylation of the B subfamily of ATP-binding cassette transporter proteins (ABCBs). Our results demonstrate that involvement of OsMOGS in N-glycan formation is required for auxin-mediated root development in rice.

Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections.

Sadat et al. reported in the 24 April 2014 issue of the New England Journal of Medicine that patients genetically deficient in the gene encoding mannosyl-oligosaccharide glucosidase (MOGS), also known as endoplasmic reticulum (ER) glucosidase I, manifested a severe hypogammaglobulinaemia without clinical evidence of an infectious diathesis. This paradox phenomenon is, at least in part, because the impaired N-linked glycan processing of the patients compromises their ability to support efficient replication and cellular entry of viruses. This finding unambiguously validates ER glucosidases as valuable targets for antiviral agents against a broad-spectrum of enveloped viruses.