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

20 Citations (Scopus)

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

Fingerprint

Heparitin Sulfate
Mutation
Zebrafish
Stem Cells
Exome
Induced Pluripotent Stem Cells
Glycosyltransferases
Fibroblast Growth Factor 2
Missense Mutation
Green Fluorescent Proteins
Interleukin-2
Cell Differentiation
Complementary DNA
Fibroblasts
Epithelial Cells
Phosphorylation
Lymphocytes
RNA
T-Lymphocytes
Injections

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

Cite this

Volpi, S., Yamazaki, Y., Brauer, P. M., van Rooijen, E., Hayashida, A., Slavotinek, A., ... 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

EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay. / Volpi, Stefano; Yamazaki, Yasuhiro; Brauer, Patrick M; van Rooijen, Ellen; Hayashida, Atsuko; Slavotinek, Anne; Sun Kuehn, Hye; Di Rocco, Maja; Rivolta, Carlo; Bortolomai, Ileana; Du, Likun; Felgentreff, Kerstin; Ott de Bruin, Lisa; Hayashida, Kazutaka; Freedman, George; Marcovecchio, Genni Enza; Capuder, Kelly; Rath, Prisni; Luche, Nicole; Hagedorn, Elliott J; Buoncompagni, Antonella; Royer-Bertrand, Beryl; Giliani, Silvia; Poliani, Pietro Luigi; Imberti, Luisa; Dobbs, Kerry; Poulain, Fabienne E; Martini, Alberto; Manis, John; Linhardt, Robert J; Bosticardo, Marita; Rosenzweig, Sergio Damian; Lee, Hane; Puck, Jennifer M; Zúñiga-Pflücker, Juan Carlos; Zon, Leonard; Park, Pyong Woo; Superti-Furga, Andrea; Notarangelo, Luigi D.

In: Journal of Experimental Medicine, Vol. 214, No. 3, 06.03.2017, p. 623-637.

Research output: Contribution to journalArticle

Volpi, S, Yamazaki, Y, Brauer, PM, 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, GE, Capuder, K, Rath, P, Luche, N, Hagedorn, EJ, Buoncompagni, A, Royer-Bertrand, B, Giliani, S, Poliani, PL, Imberti, L, Dobbs, K, Poulain, FE, Martini, A, Manis, J, Linhardt, RJ, Bosticardo, M, Rosenzweig, SD, Lee, H, Puck, JM, Zúñiga-Pflücker, JC, Zon, L, Park, PW, Superti-Furga, A & Notarangelo, LD 2017, 'EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay', Journal of Experimental Medicine, vol. 214, no. 3, pp. 623-637. https://doi.org/10.1084/jem.20161525
Volpi, Stefano ; Yamazaki, Yasuhiro ; Brauer, Patrick M ; van Rooijen, Ellen ; Hayashida, Atsuko ; Slavotinek, Anne ; Sun Kuehn, Hye ; Di Rocco, Maja ; Rivolta, Carlo ; Bortolomai, Ileana ; Du, Likun ; Felgentreff, Kerstin ; Ott de Bruin, Lisa ; Hayashida, Kazutaka ; Freedman, George ; Marcovecchio, Genni Enza ; Capuder, Kelly ; Rath, Prisni ; Luche, Nicole ; Hagedorn, Elliott J ; Buoncompagni, Antonella ; Royer-Bertrand, Beryl ; Giliani, Silvia ; Poliani, Pietro Luigi ; Imberti, Luisa ; Dobbs, Kerry ; Poulain, Fabienne E ; Martini, Alberto ; Manis, John ; Linhardt, Robert J ; Bosticardo, Marita ; Rosenzweig, Sergio Damian ; Lee, Hane ; Puck, Jennifer M ; Zúñiga-Pflücker, Juan Carlos ; Zon, Leonard ; Park, Pyong Woo ; Superti-Furga, Andrea ; Notarangelo, Luigi D. / EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 3. pp. 623-637.
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AU - Volpi, Stefano

AU - Yamazaki, Yasuhiro

AU - Brauer, Patrick M

AU - van Rooijen, Ellen

AU - Hayashida, Atsuko

AU - Slavotinek, Anne

AU - Sun Kuehn, Hye

AU - Di Rocco, Maja

AU - Rivolta, Carlo

AU - Bortolomai, Ileana

AU - Du, Likun

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AU - Ott de Bruin, Lisa

AU - Hayashida, Kazutaka

AU - Freedman, George

AU - Marcovecchio, Genni Enza

AU - Capuder, Kelly

AU - Rath, Prisni

AU - Luche, Nicole

AU - Hagedorn, Elliott J

AU - Buoncompagni, Antonella

AU - Royer-Bertrand, Beryl

AU - Giliani, Silvia

AU - Poliani, Pietro Luigi

AU - Imberti, Luisa

AU - Dobbs, Kerry

AU - Poulain, Fabienne E

AU - Martini, Alberto

AU - Manis, John

AU - Linhardt, Robert J

AU - Bosticardo, Marita

AU - Rosenzweig, Sergio Damian

AU - Lee, Hane

AU - Puck, Jennifer M

AU - Zúñiga-Pflücker, Juan Carlos

AU - Zon, Leonard

AU - Park, Pyong Woo

AU - Superti-Furga, Andrea

AU - Notarangelo, Luigi D

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N2 - 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.

AB - 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.

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KW - Bone Diseases, Developmental

KW - Child, Preschool

KW - Developmental Disabilities

KW - Female

KW - Heparitin Sulfate

KW - Humans

KW - Immunologic Deficiency Syndromes

KW - Induced Pluripotent Stem Cells

KW - Infant

KW - Lymphocytes

KW - Mutation

KW - N-Acetylglucosaminyltransferases

KW - Zebrafish

KW - Journal Article

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DO - 10.1084/jem.20161525

M3 - Article

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VL - 214

SP - 623

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JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

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