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

Volpi, Stefano and Yamazaki, Yasuhiro and Brauer, Patrick M. and van Rooijen, Ellen and Hayashida, Atsuko and Slavotinek, Anne and Sun Kuehn, Hye and Di Rocco, Maja and Rivolta, Carlo and Bortolomai, Ileana and Du, Likun and Felgentreff, Kerstin and Ott de Bruin, Lisa and Hayashida, Kazutaka and Freedman, George and Marcovecchio, Genni Enza and Capuder, Kelly and Rath, Prisni and Luche, Nicole and Hagedorn, Elliott J. and Buoncompagni, Antonella and Royer-Bertrand, Beryl and Giliani, Silvia and Poliani, Pietro Luigi and Imberti, Luisa and Dobbs, Kerry and Poulain, Fabienne E. and Martini, Alberto and Manis, John and Linhardt, Robert J. and Bosticardo, Marita and Rosenzweig, Sergio Damian and Lee, Hane and Puck, Jennifer M. and Zúñiga-Pflücker, Juan Carlos and Zon, Leonard and Park, Pyong Woo and Superti-Furga, Andrea and Notarangelo, Luigi D.. (2017) EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay. Journal of Experimental Medicine, 214 (3). pp. 623-637.

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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.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Rockefeller University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:02 Mar 2021 14:05
Deposited On:02 Mar 2021 14:05

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