<i>EXTL3</i> mutations cause skeletal dysplasia, immune deficiency, and developmental delay

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 <i>EXTL3</i> cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the <i>extl3</i>-mutant zebrafish (<i>box</i>) with Tg(<i>rag2:green fluorescent protein</i>) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human <i>EXTL3</i> 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 <i>EXTL3</i> 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.