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

By Stefano Volpi, Y. Yamazaki, Patrick M. Brauer, Ellen van Rooijen, A. Hayashida, A. Slavotinek, Hye Sun Kuehn, M. Di Rocco, C. Rivolta, I. Bortolomai and 29 more. 2017

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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.

Subfields: Cell Biology, Molecular Biology

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Citations in the corpus

An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case report (2022, methodology): “To date, ISDNA has been described through the elaboration of 14 cases, incidentally reported in the same year (in 2017), by three separate groups [4, 6, 8].”