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.
Original language | English |
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Pages (from-to) | 623-637 |
Number of pages | 15 |
Journal | Journal of Experimental Medicine |
Volume | 214 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 6 2017 |
Keywords
- Animals
- Bone Diseases, Developmental
- Child, Preschool
- Developmental Disabilities
- Female
- Heparitin Sulfate
- Humans
- Immunologic Deficiency Syndromes
- Induced Pluripotent Stem Cells
- Infant
- Lymphocytes
- Mutation
- N-Acetylglucosaminyltransferases
- Zebrafish
- Journal Article