Congenital disorders of glycosylation. Part I. Defects of protein N-glycosylation.

Abstract

Glycosylation is the most common chemical process of protein modification and occurs in every living cell. Disturbances of this process may be either congenital or acquired. Congenital disorders of glycosylation (CDG) are a rapidly growing disease family, with about 50 disorders reported since its first clinical description in 1980. Most of the human diseases have been discovered recently. CDG result from defects in the synthesis of the N-and Oglycans moiety of glycoproteins, and in the attachment to the polypeptide chain of proteins. These defects have been found in the activation, presentation, and transport of sugar precursors, in the enzymes responsible for glycosylation, and in proteins that control the traffic of component. There are two main types of protein glycosylation: N-glycosylation and O-glycosylation. Most diseases are due to defects in the N-glycosylation pathway. For the sake of convenience, CDG were divided into 2 types, type I and II. CDG can affect nearly all organs and systems. The considerable variability of clinical features makes it difficult to recognize patients with CDG. Diagnosis can be made on the basis of abnormal glycosylation display. In this paper, an overview of CDG with a new nomenclature limited to the group of protein Nglycosylation disorders, clinical phenotype and diagnostic approach, have been presented. The location, reasons for defects, and the number of cases have been also described. This publication aims to draw attention to the possibility of occurrence of CDG in each multisystem disorder with an unknown origin.

A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2

“…S2), which is equivalent to the most common genotype ( PMM2 R141H/F119L ) found in human patients with PMM2-CDG (Supplementary Material, Fig. S3) (2,13–17). Our model is distinct from a previously described Pmm2 mouse model ( Pmm2 R137H/F118L ), in which the F118L mutation is equivalent to a synthetic mutation F122L in the human PMM2 protein (12).…”

“…Phosphomannomutase 2 (PMM2)-CDG (previously known as CDG-Ia, OMIM Entry No. 212065) is the most commonly diagnosed type and is caused by loss-of-function mutations in PMM2 (2–4). PMM2 is an indispensable enzyme that catalyzes an early step of the N-glycosylation pathway by converting mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P), which is the precursor of guanosine diphosphate mannose (GDP-mannose), and is necessary for the production of dolichol-linked oligosaccharides (DLOs) and a myriad of N-glycans (Supplementary Material, Fig.…”

Factor VIII and vWF deficiency in STT3A‐CDG

“…Congenital disorders of glycosylation (CDG) are a genetically and clinically heterogeneous group of diseases involving various defects in glycosylation pathways. One of the most ubiquitous pathways, N‐glycosylation, involves the covalent attachment of glycans to the side chain amide group of asparagine (Asn) residues within a consensus Asn‐X‐Ser/Thr (X ≠ Pro) acceptor site in the lumen of the endoplasmic reticulum (ER), trimming of terminal glucose residues, and further modification of the N‐glycan chain within the Golgi . The transfer of the glycan chain from the dolichol phosphate to the peptide chain is catalyzed by the oligosaccharyltransferase (OST) complex, a transmembrane enzyme complex in the ER.…”

A case for protein-level and site-level specificity in glycoproteomic studies of disease

“…In the case of some types of CDGs, site occupancy analysis seems to be particularly useful, because a few of these disorders tend to result in inefficient glycosylation. CDG type-I (CDG-I) is a class of inherited diseases where there is a deficiency in the N-glycan biosynthesis pathway, typically leading to insufficient glycosylation [12,14]. There are also type-II CDGs which involve defects in the trimming and elongation processes of N-glycans, as well as CDGs involving defects in O-glycosylation [15].…”

“…Aberrant patterns of glycosylation have been noted in conjunction with a variety of diseases. For example, congenital disorders of glycosylation (CDG), autoimmune disorders, neurodegenerative diseases, and a variety of cancers have all been observed to impact the glycoproteome on some level [12][13][14][15][16][17]. While these observations have provoked interest in the exploitation of glycoproteins as diagnostic or prognostic reporters, the identification of relevant, specific, sensitive, and robust biomarkers poses a complicated and demanding task.…”