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. Hagedorn; Antonella Buoncompagni; Beryl Royer-Bertrand; Silvia Clara Giliani; Pietro Luigi Poliani; Luisa Imberti; Kerry Dobbs; Fabienne E Poulain; Alberto Martini; John P Manis; Robert J Linhardt; Marita Bosticardo; Sergio Damian Rosenzweig; Hane Lee; Jennifer M Puck; Juan Carlos Zúñiga-Pflücker; Leonard I. Zon; Pyong Woo Park; Andrea Superti-Furga; Luigi D Notarangelo

doi:10.1084/jem.20161525

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 Clara Giliani, Pietro Luigi Poliani, Luisa Imberti, Kerry Dobbs, Fabienne E Poulain, Alberto Martini, John P Manis, Robert J Linhardt, Marita Bosticardo, Sergio Damian Rosenzweig, Hane Lee, Jennifer M Puck, Juan Carlos Zúñiga-Pflücker, Leonard I. Zon, Pyong Woo Park, Andrea Superti-Furga, Luigi D Notarangelo

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	623-637
Number of pages	15
Journal	Journal of Experimental Medicine
Volume	214
Issue number	3
DOIs	https://doi.org/10.1084/jem.20161525
Publication status	Published - 2017
Externally published	Yes

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

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10.1084/jem.20161525

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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

@article{bb56aff205f7472c81028eeeda9b957d,

title = "EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay",

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.",

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",

author = "Stefano Volpi and Yasuhiro Yamazaki and Brauer, {Patrick M.} and {van Rooijen}, Ellen and Atsuko Hayashida and Anne Slavotinek and {Sun Kuehn}, Hye and {Di Rocco}, Maja and Carlo Rivolta and Ileana Bortolomai and Likun Du and Kerstin Felgentreff and {Ott de Bruin}, Lisa and Kazutaka Hayashida and George Freedman and Marcovecchio, {Genni Enza} and Kelly Capuder and Prisni Rath and Nicole Luche and Hagedorn, {Elliott J.} and Antonella Buoncompagni and Beryl Royer-Bertrand and Giliani, {Silvia Clara} and Poliani, {Pietro Luigi} and Luisa Imberti and Kerry Dobbs and Poulain, {Fabienne E} and Alberto Martini and Manis, {John P} and Linhardt, {Robert J} and Marita Bosticardo and Rosenzweig, {Sergio Damian} and Hane Lee and Puck, {Jennifer M} and Z{\'u}{\~n}iga-Pfl{\"u}cker, {Juan Carlos} and Zon, {Leonard I.} and Park, {Pyong Woo} and Andrea Superti-Furga and Notarangelo, {Luigi D}",

note = "Publisher Copyright: {\textcopyright} 2017 Volpi et al.",

year = "2017",

doi = "10.1084/jem.20161525",

language = "English",

volume = "214",

pages = "623--637",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "3",

}

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, SC, Poliani, PL, Imberti, L, Dobbs, K, Poulain, FE, Martini, A, Manis, JP, Linhardt, RJ, Bosticardo, M, Rosenzweig, SD, Lee, H, Puck, JM, Zúñiga-Pflücker, JC, Zon, LI, 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

TY - JOUR

T1 - EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay

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

AU - Felgentreff, Kerstin

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 Clara

AU - Poliani, Pietro Luigi

AU - Imberti, Luisa

AU - Dobbs, Kerry

AU - Poulain, Fabienne E

AU - Martini, Alberto

AU - Manis, John P

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 I.

AU - Park, Pyong Woo

AU - Superti-Furga, Andrea

AU - Notarangelo, Luigi D

PY - 2017

Y1 - 2017

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.

KW - Animals

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

U2 - 10.1084/jem.20161525

DO - 10.1084/jem.20161525

M3 - Article

C2 - 28148688

SN - 0022-1007

VL - 214

SP - 623

EP - 637

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 3

ER -

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

Abstract

Keywords

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