Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

Abstract

Glycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways not only revealed tremendous diversity in functional impairments, but also pointed to phenotypic similarities, emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview of the significance of glycosylation in human development and physiology. Congenital disorders of glycosylation -a consice chart of glycocalyx dysfunctionThierry Hennet, Jürg Cabalzar Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland AbstractGlycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways has revealed a tremendous diversity of functional impairments bus also pointed to phenotypic similarities emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview on the significance of glycosylation in human development and physiology. Highlights Congenital disorders underline the role of glycosylation in human development.  Next-gen sequencing techniques expanded the discovery of glycosylation gene defects.  The clinical variability of glycosylation disorders implies they are underdiagnosed. Glycosylation disordersGlycosylation is by far the most complex form of protein [1,2] and lipid modification [3,4] in all domains of life. The tremendous diversity of glycoconjugate structures resulting from intricate biosynthetic pathways is a major factor hampering the assignment of functions to glycans chains. Much has been learnt from the study of disrupted glycosylation genes in model organisms, thereby establishing numerous essential contributions of glycans in regulating cell and organ functions [5]. The study of human diseases of glycosylation brings additional insights by providing a more differentiated view on glycan functions. Indeed, most human mutations are hypomorphic, thus causing partial loss of glycosylation reactions that lead to variable clinical manifestations.Diseases of glycosylation are also referred to as congenital disorders of glycosylation (CDG). Given the heterogeneity of glycans, the clinical scope of CDG is considerable, ranging from nearly normal phenotypes to sever...

The atomic structure of a eukaryotic oligosaccharyltransferase complex

“…Almost two-third of proteins include the NXS/T sequon and 65–75% of them are glycoproteins 4,7 . Mutations in the OST proteins cause a family of diseases known as congenital disorders of glycosylation 8 .…”

“…The structures of Ost4 were solved by NMR 19,20 . Biochemical studies suggested that Ost1 and Wbp1 recognize acceptor and donor substrates, respectively 8,21,22 . The structures of the eukaryotic OST have been limited to low-resolution EM reconstructions, hindering a mechanistic understanding of protein N-glycosylation in eukaryotes 23–26 .…”

Members of the Galectin Network with Deviations from the Canonical Sequence Signature. 1. <i>G</i>alectin-<i>R</i>elated <i>I</i>nter-<i>F</i>iber Prote<i>in</i> (GRIFIN)

“…Just as an intricate synthetic apparatus ensures to have a broad panel of 'code words' available (3)(4)(5)(6)(7)(8), the same is true for reaching diversity on the level of 'readers' of the sugar code: more than a dozen protein folds have developed the ability to specifically bind glycans (9)(10)(11)(12)(13)(14). Among them, the β-sandwich motif is a (15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families

“…HME belongs to the group of glycosaminoglycan biosynthesis deficiencies associated with skeletal and connective tissue disorders (Hennet and Cabalzar, 2015). The inheritance of HME is autosomal dominant and most patients have non-sense mutation in the EXT1 gene on chromosome 8q24 or EXT2 gene on chromosome 11p11-13 encoding exostosin glycosyltransferase 1 and 2 (EXT1; OMIM *608177 and EXT2; OMIM *608210) (Wuyts et al, 1998;Francannet et al, 2001).…”