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

J Exp Med. 2017 Mar 6;214(3):623-637. doi: 10.1084/jem.20161525. Epub 2017 Feb 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Bone Diseases, Developmental / etiology*
  • Child, Preschool
  • Developmental Disabilities / etiology*
  • Female
  • Heparitin Sulfate / physiology
  • Humans
  • Immunologic Deficiency Syndromes / etiology*
  • Induced Pluripotent Stem Cells / cytology
  • Infant
  • Lymphocytes / physiology
  • Mutation*
  • N-Acetylglucosaminyltransferases / genetics*
  • Zebrafish


  • EXTL3 protein, human
  • Heparitin Sulfate
  • N-Acetylglucosaminyltransferases