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

Details

Ressource 1Download: 28148688_BIB_A5331400A820.pdf (2554.20 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_A5331400A820
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.
Journal
The Journal of experimental medicine
Author(s)
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.
ISSN
1540-9538 (Electronic)
ISSN-L
0022-1007
Publication state
Published
Issued date
06/03/2017
Peer-reviewed
Oui
Volume
214
Number
3
Pages
623-637
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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.

Pubmed
Web of science
Open Access
Yes
Create date
14/02/2017 11:47
Last modification date
20/08/2019 15:10
Usage data