(The Rockefeller University Press, 2017) 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; 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; Superti-Furga, Andrea; Notarangelo, Luigi D.
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.
