Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

Abstract

Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides that constitute the carbohydrate moiety covalently attached to the protein core of proteoglycans, macromolecules present on the cell surface and in the extracellular matrix. Several genetic disorders of bone and connective tissue are caused by mutations in genes encoding for glycosyltransferases, sulfotransferases and transporters that are responsible for the synthesis of sulfated GAGs. Phenotypically, these disorders all reflect alterations in crucial biological functions of GAGs in the development, growth and homoeostasis of cartilage and bone. To date, up to 27 different skeletal phenotypes have been linked to mutations in 23 genes encoding for proteins involved in GAG biosynthesis. This review focuses on recent genetic, molecular and biochemical studies of bone and connective tissue disorders caused by GAG synthesis defects. These insights and future research in the field will provide a deeper understanding of the molecular pathogenesis of these disorders and will pave the way for developing common therapeutic strategies that might be targeted to a range of individual phenotypes.

Growth patterns for untreated individuals with MPS I: Report from the international MPS I registry

“…Growth abnormalities are key manifestations of all of the mucopolysaccharidoses as well as many other skeletal dysplasias caused by genetic defects in glycosaminoglycan synthesis, such as hereditary multiple exostoses (Zak, Crawford, & Esko, ), Desbuquois dysplasia type 1 (Paganini, Monti, et al, ), among others (Mizumoto, Ikegawa, & Sugahara, ; Paganini, Costantini, et al, ). These clinical observations emphasize the importance of glycosaminoglycan homeostasis for normal growth (Clarke, ).…”

CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage

“…These properties contribute to the maintenance of the optimal compressive stiffness and tissue hydration [21,22]. Similar histological defects have also been observed in humans and animals that are deficient in GAG synthesis and metabolism [14,15]. Therefore, the physical properties of ECM conferred by GAGs may be important to maintain the proper columnar alignment and typical flat shape of proliferating chondrocytes.…”

“…The causative gene for DD type 1 and Kim variant has been identified as CANT1 , which encodes calcium‐activated nucleotidase 1 [6–8], and the causative gene for DD type 2 has been identified as XYLT1 , which encodes xylosyltransferase 1 [9,10]. In the formation of proteoglycans, a family of extracellular macromolecules comprised of glycosaminoglycan (GAG) chains linked to a central core protein [11,12], xylosyltransferase 1 functions as the initiator of GAG chain biosynthesis by transferring xylose from UDP xylose to the core protein [13–15]. Meanwhile, CANT1 is a nucleotidase that preferentially hydrolyzes UDP to UMP and phosphate [16–18].…”

“…Glycosaminoglycans are large linear polysaccharides constructed of repeating disaccharides and can be classified into chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), and heparin, based on their disaccharide units. GAG chains are modified by sulfation at various hydroxyl group positions and also by the epimerization of uronic acid residues [13–15]. This structural diversity plays important roles in a range of biological functions including development, growth, and homeostasis of skeletal tissues.…”

“…This structural diversity plays important roles in a range of biological functions including development, growth, and homeostasis of skeletal tissues. In humans and animals, many skeletal dysplasias are caused by mutations in genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs [14,15]…”