Alterations in glycosaminoglycan biosynthesis associated with the Ehlers-Danlos Syndromes.

Fiche publication

Date publication

août 2022

Journal

American journal of physiology. Cell physiology

Auteurs

Membres identifiés du Cancéropôle Est :
Dr FOURNEL-GIGLEUX Sylvie

Tous les auteurs :
Syx D, Delbaere S, Bui C, De Clercq A, Larson G, Mizumoto S, Kosho T, Fournel-Gigleux S, Malfait F

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35993517

Résumé

Proteoglycans consist of a core protein substituted with one or more glycosaminoglycan (GAG) chains and execute versatile functions during many physiological and pathological processes. The biosynthesis of GAG chains is a complex process that depends on the concerted action of a variety of enzymes. Central to the biosynthesis of heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (CS/DS) GAG chains is the formation of a tetrasaccharide linker region followed by biosynthesis of HS or CS/DS-specific repeating disaccharide units, which then undergo modifications and epimerisation. The importance of these biosynthetic enzymes is illustrated by several severe pleiotropic disorders that arise upon their deficiency. The Ehlers-Danlos syndrome (EDS) constitute a special group among these disorders. While most EDS types are caused by defects in fibrillar types I, III or V collagen, or their modifying enzymes, a few rare EDS types have recently been linked to defects in GAG biosynthesis. Spondylodysplastic EDS (spEDS) is caused by defective formation of the tetrasaccharide linker region, either due to β4GalT7 or β3GalT6 deficiency, whereas musculocontractural EDS (mcEDS) results from deficiency of D4ST1 or DS-epi1, impairing DS formation. This narrative review highlights the consequences of GAG deficiency in these specific EDS types, summarizes the associated phenotypic features and the molecular spectrum of reported pathogenic variants and defines the current knowledge on the underlying pathophysiological mechanisms based on studies in patient-derived material, in vitro analyses and animal models.