Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

Abstract

Glycosaminoglycans (GAGs) are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases and sulfotransferases. The structural diversity of GAG polysaccharides, including their sulfation patterns and sequential arrangements, is essential for a wide range of biological activities such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Studies using knockout mice of enzymes responsible for the biosynthesis of the GAG side chains of proteoglycans have revealed their physiological functions. Furthermore, mutations in the human genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs cause a number of genetic disorders including chondrodysplasia, spondyloepiphyseal dysplasia, and Ehlers-Danlos syndromes. This review focused on the increasing number of glycobiological studies on knockout mice and genetic diseases caused by disturbances in the biosynthetic enzymes for GAGs.

Biological roles of glycans

“…In general, complete elimination of major classes or subclasses of glycans tends to result in embryonic lethality, while defects in outer terminal structures often give viable organisms with defects in specific functions and/or specific cell types, although these impacts are often species specific. As an example, null alleles preventing the synthesis of the core glycosaminoglycan backbone of heparan sulfate causes embryonic lethality (421)(422), but the prevention of proper sulfation of this backbone can give living mice with specific defects (422)(423)(424)(425)(426)(427). When embryonic lethality makes it difficult to define specific biological roles, tissue-specific targeted genetic alterations became important (428)(429)(430).…”

Disturbed Laminar Blood Flow Vastly Augments Lipoprotein Retention in the Artery Wall

“…[24][25][26][27] Furthermore, we predefined a gene set of enzymes responsible for the synthesis of the glycosaminoglycan tetrasaccharide linker, chondroitin sulfate glycosaminoglycan and sulfation of chondroitin sulfate glycosaminoglycans. 28 An over-representation analysis was performed using the GO-Elite software, and all 4 predefined gene sets were significantly over-represented in the analysis (Table). For validation of the over-representation analysis, we analyzed a selection of the genes by quantitative reverse-transcriptase polymerase chain reaction ( Figure 6).…”

Inactivation of Fam20B in the dental epithelium of mice leads to supernumerary incisors

“…Inactivation of genes encoding FGF antagonists -Sprouty2 and 4led to supernumerary teeth as a result of hypersensitivity in FGF signaling (58,59). Notably, the activity changes in these signaling pathways ultimately need ectopic expression of SHH to induce supernumerary tooth formation (3,43,60). Given the regulatory roles of GAGs in mediating the WNT, BMP, FGF, and SHH signaling pathways, and the correlation between the activity changes of these pathways and the supernumerary teeth, we speculate that the supernumerary teeth in the K14-Cre;Fam20B flox/flox mice may be associated with the activity changes in one or several preceding pathways that are tightly regulated by the GAGs.…”

“…The assembly of GAG chains is initiated by the synthesis of the GAG‐protein linkage region (GlcA β 1‐3Gal β 1‐3Gal β 1‐4Xyl β 1‐ O ‐Ser), which is formed through the sequential addition of monosaccharide residues catalyzed by respective glycosyltransferases . The repeating disaccharide of heparan sulfate, heparin, chondroitin sulfate, and dermatan sulfate is synthesized on the linkage region , followed by numerous modifications, including sulfation, epimerization, and desulfation.…”