ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder, geleophysic dysplasia 1 (GPHYSD1), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 is a matricellular protein previously shown to interact with latent transforming growth factor-β binding protein 1 and influence assembly of fibrillin 1 microfibrils. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for O-fucosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose–modified TSRs are subsequently elongated to a glucose β1-3-fucose (GlcFuc) disaccharide by β1,3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS), which is characterized by skeletal defects similar to GPHYSD1. Several ADAMTSL2 TSRs also have consensus sequences for C-mannosylation. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used MS to identify glycan modifications at predicted consensus sequences on mouse ADAMTSL2. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2−/− but not in B3GLCT−/− cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients. In contrast, secretion was significantly reduced for ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6), and S641L eliminated O-fucosylation of TSR3. These results provide evidence that abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion.

中文翻译：

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ADAMTSL2 的 O-岩藻糖基化是分泌所必需的，并且受到凝胶物理发育不良引起的突变的影响。

ADAMTSL2 突变导致常染色体隐性结缔组织疾病，即凝胶物理发育不良 1 (GPHYSD1)，其特征是身材矮小、手脚小和心脏缺陷。ADAMTSL2 是一种基质细胞蛋白，以前显示它与潜在的转化生长因子-β 结合蛋白 1 相互作用并影响原纤维蛋白 1 微原纤维的组装。ADAMTSL2 包含七个血小板反应蛋白 1 型重复序列 (TSR)，其中六个包含蛋白 O-岩藻糖基转移酶 2 (POFUT2) 进行 O-岩藻糖基化的共有序列。O-岩藻糖修饰的 TSR 随后被 β1,3-葡萄糖基转移酶 (B3GLCT) 延长为葡萄糖 β1-3-岩藻糖 (GlcFuc) 二糖。B3GLCT 突变导致 Peters Plus 综合征 (PTRPLS)，其特征是类似于 GPHYSD1 的骨骼缺陷。几个 ADAMTSL2 TSR 也具有 C-甘露糖基化的共有序列。六个报告的 GPHYSD1 突变发生在 TSR 内，两个位于 O-岩藻糖基化位点附近。为了研究 TSR 糖基化对 ADAMTSL2 功能的影响，我们使用 MS 来鉴定小鼠 ADAMTSL2 上预测的共有序列处的聚糖修饰。我们发现大多数 TSR 在 O-岩藻糖基化位点以高化学计量的 GlcFuc 二糖和在 C-甘露糖基化位点的可变甘露糖化学计量被修饰。POFUT2-/- 但在 B3GLCT-/- 细胞中 ADAMTSL2 分泌的缺失表明 ADAMTSL2 分泌受损不是 PTRPLS 患者骨骼缺陷的原因。相比之下，携带 GPHYSD1 突变（TSR3 中的 S641L 和 TSR6 中的 G817R）的 ADAMTSL2 的分泌显着减少，并且 S641L 消除了 TSR3 的 O-岩藻糖基化。