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EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.

机译：EXTL3突变会导致骨骼发育不良，免疫缺陷和发育延迟。

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摘要

We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.
机译：我们研究了三例严重骨骼发育不良，T细胞免疫缺陷和发育迟缓的患者。全外显子组测序显示纯合的错义突变影响了exostosin-like 3（EXTL3），这是一种参与硫酸乙酰肝素（HS）生物合成的糖基转移酶。患者来源的成纤维细胞表现出异常的HS组成并改变了成纤维细胞生长因子2信号传导，这可以通过野生型EXTL3 cDNA的过表达来挽救。患者淋巴细胞中白介素2介导的STAT5磷酸化明显降低。与tg（rag2：绿色荧光蛋白）转基因斑马鱼的extl3突变斑马鱼（框）的杂种显示胸腺造血功能缺陷，通过注入野生型人EXTL3 RNA得以挽救。患者来源的诱导多能干细胞的靶向分化显示淋巴造血祖细胞的扩增减少和胸腺上皮祖细胞分化的缺陷。这些数据确定EXTL3突变是严重的免疫缺陷伴骨骼发育异常和发育延迟的新原因，并突显了HS在胸腺细胞生成和骨骼与大脑发育中的关键作用。

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