Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Italy.
Division of Genetic Medicine, Lausanne University Hospital, University of Lausanne, Switzerland.
FEBS J. 2019 Aug;286(15):3008-3032. doi: 10.1111/febs.14984. Epub 2019 Jul 25.
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.
糖胺聚糖（GAGs）是一组异质的线性多糖，构成了糖胺聚糖蛋白聚糖的碳水化合物部分，糖胺聚糖蛋白聚糖是存在于细胞表面和细胞外基质中的大分子。几种骨骼和结缔组织的遗传疾病是由编码糖基转移酶、硫酸转移酶和转运体的基因突变引起的，这些基因负责合成硫酸化 GAGs。表型上，这些疾病都反映了 GAGs 在软骨和骨骼发育、生长和动态平衡中的关键生物学功能的改变。迄今为止，已经有 27 种不同的骨骼表型与 23 种编码参与 GAG 生物合成的蛋白质的基因突变相关。这篇综述重点介绍了 GAG 合成缺陷引起的骨骼和结缔组织疾病的最新遗传、分子和生化研究。这些见解和该领域的未来研究将为深入了解这些疾病的分子发病机制提供依据，并为开发针对一系列个体表型的通用治疗策略铺平道路。
