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

Stefano Volpi, Yasuhiro Yamazaki, Patrick M Brauer, Ellen van Rooijen, Atsuko Hayashida, Anne Slavotinek, Hye Sun Kuehn, Maja Di Rocco, Carlo Rivolta, Ileana Bortolomai, Likun Du, Kerstin Felgentreff, Lisa Ott de Bruin, Kazutaka Hayashida, George Freedman, Genni Enza Marcovecchio, Kelly Capuder, Prisni Rath, Nicole Luche, Elliott J HagedornAntonella Buoncompagni, Beryl Royer-Bertrand, Silvia Giliani, Pietro Luigi Poliani, Luisa Imberti, Kerry Dobbs, Fabienne E Poulain, Alberto Martini, John Manis, Robert J Linhardt, Marita Bosticardo, Sergio Damian Rosenzweig, Hane Lee, Jennifer M Puck, Juan Carlos Zúñiga-Pflücker, Leonard Zon, Pyong Woo Park, Andrea Superti-Furga, Luigi D Notarangelo

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)623-637
Number of pages15
JournalJournal of Experimental Medicine
Volume214
Issue number3
DOIs
Publication statusPublished - 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

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  • Cite this

    Volpi, S., Yamazaki, Y., Brauer, P. M., van Rooijen, E., Hayashida, A., Slavotinek, A., Sun Kuehn, H., Di Rocco, M., Rivolta, C., Bortolomai, I., Du, L., Felgentreff, K., Ott de Bruin, L., Hayashida, K., Freedman, G., Marcovecchio, G. E., Capuder, K., Rath, P., Luche, N., ... Notarangelo, L. D. (2017). EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay. Journal of Experimental Medicine, 214(3), 623-637. https://doi.org/10.1084/jem.20161525