Volpi Stefano, Yamazaki Yasuhiro, Brauer Patrick M, van Rooijen Ellen, Hayashida Atsuko, Slavotinek Anne, Sun Kuehn Hye, Di Rocco Maja, Rivolta Carlo, Bortolomai Ileana, Du Likun, Felgentreff Kerstin, Ott de Bruin Lisa, Hayashida Kazutaka, Freedman George, Marcovecchio Genni Enza, Capuder Kelly, Rath Prisni, Luche Nicole, Hagedorn Elliott J, Buoncompagni Antonella, Royer-Bertrand Beryl, Giliani Silvia, Poliani Pietro Luigi, Imberti Luisa, Dobbs Kerry, Poulain Fabienne E, Martini Alberto, Manis John, Linhardt Robert J, Bosticardo Marita, Rosenzweig Sergio Damian, Lee Hane, Puck Jennifer M, Zúñiga-Pflücker Juan Carlos, Zon Leonard, Park Pyong Woo, Superti-Furga Andrea, Notarangelo Luigi D
Unita' Operativa Pediatria 2, Istituto Giannina Gaslini, 16148 Genoa, Italy.
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892.
J Exp Med. 2017 Mar 6;214(3):623-637. doi: 10.1084/jem.20161525. Epub 2017 Feb 1.
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 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the -mutant zebrafish () with Tg() transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human 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 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.
我们研究了三名患有严重骨骼发育不良、T细胞免疫缺陷和发育迟缓的患者。全外显子组测序揭示了影响外切糖苷酶样3（EXTL3）的纯合错义突变，EXTL3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显示HS组成异常和成纤维细胞生长因子2信号改变，野生型cDNA的过表达可使其恢复。患者淋巴细胞中白细胞介素-2介导的STAT5磷酸化明显降低。将突变的斑马鱼（）与Tg（）转基因斑马鱼杂交显示胸腺生成缺陷，注射野生型人类RNA可使其恢复。患者来源的诱导多能干细胞的定向分化显示淋巴细胞造血祖细胞的扩增减少以及胸腺上皮祖细胞分化缺陷。这些数据确定突变是导致严重免疫缺陷伴骨骼发育不良和发育迟缓的新原因，并强调了HS在胸腺生成以及骨骼和大脑发育中的关键作用。
