EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay PMID: 28148688

ADC Targets in Oncology

2026-04-10

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.

Stefano Volpi ¹ , Yasuhiro Yamazaki ² , Patrick M Brauer ³ , Ellen van Rooijen ⁴ , Atsuko Hayashida ⁵ , Anne Slavotinek ⁶ , Hye Sun Kuehn ⁷ , Maja Di Rocco ⁸ , Carlo Rivolta ⁹ , Ileana Bortolomai ¹⁰ ¹¹ , Likun Du ¹² , Kerstin Felgentreff ¹² , Lisa Ott de Bruin ¹² , Kazutaka Hayashida ⁵ , George Freedman ¹³ , Genni Enza Marcovecchio ¹⁰ , Kelly Capuder ¹² , Prisni Rath ¹⁴ , Nicole Luche ¹² , Elliott J Hagedorn ⁴ , Antonella Buoncompagni ¹ , Beryl Royer-Bertrand ⁹ ¹⁵ , Silvia Giliani ¹⁶ , Pietro Luigi Poliani ¹⁷ , Luisa Imberti ¹⁸ , Kerry Dobbs ² , Fabienne E Poulain ¹⁹ , Alberto Martini ¹ , John Manis ²⁰ , Robert J Linhardt ²¹ , Marita Bosticardo ¹⁰ , Sergio Damian Rosenzweig ⁷ , Hane Lee ²² , Jennifer M Puck ¹³ , Juan Carlos Zúñiga-Pflücker ³ , Leonard Zon ⁴ , Pyong Woo Park ⁵ , Andrea Superti-Furga ²³ , Luigi D Notarangelo ²⁴

Affiliations

1. Unita' Operativa Pediatria 2, Istituto Giannina Gaslini, 16148 Genoa, Italy.
2. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892.
3. Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M5S, Canada.
4. Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
5. Division of Respiratory Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
6. Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143.
7. Department of Laboratory Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, 20892.
8. Unit of Rare Diseases, Department of Pediatrics, Istituto Giannina Gaslini, 16148 Genoa, Italy.
9. Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1015 Lausanne, Switzerland.
10. San Raffaele Telethon Institute for Gene Therapy, Istituto di Ricerca e Cura a Carattere Scientifico San Raffaele Scientific Institute, 20132 Milan, Italy.
11. Consiglio Nazionale delle Ricerche-Istituto di Ricerca Genetica e Biomedica, Milan Unit, 20138 Milan, Italy.
12. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
13. Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143.
14. Tata Consultancy Services Innovation Labs, Telangana 500081, India.
15. Division of Genetic Medicine, Lausanne University Hospital, University of Lausanne, 1015 Lausanne, Switzerland.
16. A. Nocivelli Institute for Molecular Medicine, University of Brescia, 25123 Brescia, Italy.
17. Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
18. Centro di ricerca emato-oncologica AIL, Spedali Civili, 25123 Brescia, Italy.
19. Department of Biological Sciences, University of South Carolina, Columbia, SC 29208.
20. Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
21. Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180.
22. Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
23. Division of Genetic Medicine, Lausanne University Hospital, University of Lausanne, 1015 Lausanne, Switzerland [email protected] [email protected].
24. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892 [email protected] [email protected].

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.