Heparan sulfate belongs to the group of glycosaminoglycans (GAGs), highly sulfated linear polysaccharides. Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is one of several specialized enzymes required for heparan sulfate synthesis and catalyzes the transfer of the sulfate groups to the sugar moiety of heparan sulfate. We report bi-allelic pathogenic variants in HS2ST1 in four individuals from three unrelated families. Affected individuals showed facial dysmorphism with coarse face, upslanted palpebral fissures, broad nasal tip, and wide mouth, developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, flexion contractures, brachydactyly of hands and feet with broad fingertips and toes, and uni- or bilateral renal agenesis in three individuals. HS2ST1 variants cause a reduction in HS2ST1 mRNA and decreased or absent heparan sulfate 2-O-sulfotransferase 1 in two of three fibroblast cell lines derived from affected individuals. The heparan sulfate synthesized by the individual 1 cell line lacks 2-O-sulfated domains but had an increase in N- and 6-O-sulfated domains demonstrating functional impairment of the HS2ST1. As heparan sulfate modulates FGF-mediated signaling, we found a significantly decreased activation of the MAP kinases ERK1/2 in FGF-2-stimulated cell lines of affected individuals that could be restored by addition of heparin, a GAG similar to heparan sulfate. Focal adhesions in FGF-2-stimulated fibroblasts of affected individuals concentrated at the cell periphery. Our data demonstrate that a heparan sulfate synthesis deficit causes a recognizable syndrome and emphasize a role for 2-O-sulfated heparan sulfate in human neuronal, skeletal, and renal development.

硫酸乙酰肝素属于糖胺聚糖 (GAG) 组，即高度硫酸化的线性多糖。硫酸乙酰肝素 2 - O-磺基转移酶 1 (HS2ST1) 是硫酸乙酰肝素合成所需的几种特殊酶之一，可催化硫酸根基团转移到硫酸乙酰肝素的糖部分。我们报告了来自三个不相关家族的四个人的HS2ST1双等位基因致病变异。受影响的个体表现出面部畸形，面部粗糙，睑裂上翘，鼻尖宽，嘴巴宽，发育迟缓和/或智力障碍，胼胝体发育不全或发育不全，屈曲挛缩，手脚短指，指尖和脚趾宽，以及三个人的单侧或双侧肾发育不全。HS2ST1变体导致源自受影响个体的三个成纤维细胞系中的两个中HS2ST1 mRNA 减少和硫酸乙酰肝素 2 - O-磺基转移酶 1 减少或缺失。由单个 1 细胞系合成的硫酸乙酰肝素缺乏 2 - O-硫酸化结构域，但N-和 6- O增加-硫酸化结构域表明 HS2ST1 的功能障碍。由于硫酸乙酰肝素调节 FGF 介导的信号传导，我们发现受影响个体的 FGF-2 刺激细胞系中 MAP 激酶 ERK1/2 的活化显着降低，可以通过添加肝素（一种类似于硫酸乙酰肝素的 GAG）来恢复。受影响个体的 FGF-2 刺激的成纤维细胞中的粘着斑集中在细胞外围。我们的数据表明硫酸乙酰肝素合成缺陷会导致可识别的综合征，并强调 2 - O-硫酸乙酰肝素在人类神经元、骨骼和肾脏发育中的作用。