期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 3, 页码 623-637出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161525
关键词
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资金
- Telethon Network of Genetic Biobanks [GTB12001]
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)
- NIAID, NIH [5R21AI113459]
- Italian Ministry of Health [PE-2011-02347329]
- Swiss National Science Foundation [156260]
- National Institute of Neurological Disorders and Stroke, NIH [R00NS083714]
- Faculte de Biologie et Medecine of the University of Lausanne
- Krembil Foundation
- Canada Research Chair in Developmental Immunology
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.
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