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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.
Most proteins, including immunoglobulins, human virus receptors, and viral-coded proteins, are post-translationally modified with sugars or sugar chains that are generically referred to as glycans. Glycans are primarily classified as N-linked or O-linked oligosaccharides, depending on whether they are bound to the amide group of asparagine (N-linked) or the hydroxyl group of serine or threonine (O-linked). Glycans are associated with protein conformation, folding, solubility, stability, half-life, and antigenicity and are the moieties recognized by glycan-binding proteins. The congenital disorders of glycosylation (CDGs) are genetic disorders affecting the N-glycosylation process. CDGs are divided into defects in the synthesis of N-glycans (CDG-I) and defects in the processing of N-glycans (CDG-II). CDG-IIb (Online Mendelian Inheritance in Man database number, 606056) is caused by mutations in the gene encoding MOGS (also known as glucosidase 1). MOGS is an enzyme that is expressed in the endoplasmic reticulum and is involved in the trimming of N-glycans.1 A single case of CDG-IIb has been reported; the patient died at the age of 74 days from severe neurologic complications.2 In this study, we evaluated the immune system and susceptibility to viral diseases in two siblings with CDG-IIb who presented with severe hypogammaglobulinemia but not many infections.
Furthermore, as suggested by the effects of castanospermine on viral glycoproteins (Figure 2B), there is a strong potential benefit of using inhibitors of MOGS as a means of controlling viral infections, especially those that pose a threat of rapid global spreading. Previous in vitro studies have shown that MOGS inhibitors such as castanospermine, N-butyldeoxynojirimycin (miglustat; previously known as NB-DNJ), or deoxynojirimycin can reduce viral replication in HIV infection, dengue, herpes simplex virus type 2 infection, and hepatitis C.
Early in life, they each had a complex disorder characterized by dysmorphic facial features, generalized hypotonia, seizures, global developmental delay, cerebral atrophy, a small corpus callosum, optic-nerve atrophy, sensorineural hearing loss, hypoplastic genitalia, chronic constipation, and recurrent bone fractures; severe hypogammaglobulinemia was also diagnosed. The patients were evaluated for the frequency of febrile episodes
This could be an evolutionary step towards humans becoming resistant to these diseases that are meant to wipe us out. Granted the other complications are awful, but mutation and evolution do not happen overnight.....