Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human
Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human
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DOI：
10.1038/nm1655
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发表时间：
2007-11-01
期刊：
影响因子：
82.9
通讯作者：
Ikegawa, Shiro
中科院分区：
文献类型：
--
作者：
Hiraoka, Shuichi;Furuichi, Tatsuya;Ikegawa, Shiro
蛋白聚糖是由连接到中心核心蛋白的重复二糖的糖胺聚糖链组成的细胞外大分子家族（1，2）。蛋白聚糖在软骨形成和骨骼发育中具有关键作用。软骨蛋白聚糖中发现的糖胺聚糖链主要由硫酸软骨素组成（3）。硫酸软骨素链的完整性对软骨蛋白聚糖的功能很重要，然而，硫酸软骨素在哺乳动物中的代谢仍然知之甚少。溶质载体-35 D1（SLC35D1）基因（SLC35D1）编码内质网核苷酸-糖转运蛋白（NST），其可能转运硫酸软骨素生物合成所需的底物（4，5）。在这里，我们创造了Slc35d1缺陷小鼠，这些小鼠发展出致命形式的骨骼发育不良，肢体和面部结构严重缩短。纯合子突变小鼠的骺软骨显示圆形软骨细胞增殖区减少，基质稀少，蛋白多糖聚集体减少。这些小鼠具有由硫酸软骨素生物合成缺陷引起的短而稀疏的硫酸软骨素链。我们还确定了人SLC35D1的功能缺失突变导致Schneckenbecken发育不良，一种严重的骨骼发育不良。我们的研究结果突出了NST在蛋白聚糖功能和软骨代谢中的关键作用，从而揭示了骨骼疾病和糖生物学的新范式。
Proteoglycans are a family of extracellular macromolecules comprised of glycosaminoglycan chains of a repeated disaccharide linked to a central core protein(1,2). Proteoglycans have critical roles in chondrogenesis and skeletal development. The glycosaminoglycan chains found in cartilage proteoglycans are primarily composed of chondroitin sulfate(3). The integrity of chondroitin sulfate chains is important to cartilage proteoglycan function; however, chondroitin sulfate metabolism in mammals remains poorly understood. The solute carrier-35 D1 (SLC35D1) gene (SLC35D1) encodes an endoplasmic reticulum nucleotide-sugar transporter (NST) that might transport substrates needed for chondroitin sulfate biosynthesis(4,5). Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures. Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates. These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis. We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia. Our findings highlight the crucial role of NSTs in proteoglycan function and cartilage metabolism, thus revealing a new paradigm for skeletal disease and glycobiology.