ZFIN ID: ZDB-PUB-170204-9
EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay
Volpi, S., Yamazaki, Y., Brauer, P.M., van Rooijen, E., Hayashida, A., Slavotinek, A., Sun Kuehn, H., Di Rocco, M., Rivolta, C., Bortolomai, I., Du, L., Felgentreff, K., Ott de Bruin, L., Hayashida, K., Freedman, G., Marcovecchio, G.E., Capuder, K., Rath, P., Luche, N., Hagedorn, E.J., Buoncompagni, A., Royer-Bertrand, B., Giliani, S., Poliani, P.L., Imberti, L., Dobbs, K., Poulain, F.E., Martini, A., Manis, J., Linhardt, R.J., Bosticardo, M., Rosenzweig, S.D., Lee, H., Puck, J.M., Zúñiga-Pflücker, J.C., Zon, L., Park, P.W., Superti-Furga, A., Notarangelo, L.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.