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

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

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

Note: Order does not necessarily reflect citation order of authors.

Citation: Volpi, S., Y. Yamazaki, P. M. Brauer, E. van Rooijen, A. Hayashida, A. Slavotinek, H. Sun Kuehn, et al. 2017. “EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.” The Journal of Experimental Medicine 214 (3): 623-637. doi:10.1084/jem.20161525. http://dx.doi.org/10.1084/jem.20161525.
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Abstract: 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.
Published Version: doi:10.1084/jem.20161525
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339678/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492076
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