EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.
Details
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
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
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 12:47
Last modification date
20/08/2019 16:10