EXTL3mutations cause skeletal dysplasia, immune deficiency, and developmental delay.
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-typeEXTL3cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of theextl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type humanEXTL3RNA. 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 identifyEXTL3mutations 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.
Unita' Operativa Pediatria 2, Istituto Giannina Gaslini, 16148 Genoa, Italy.
Stefano
0000-0002-7129-868X
S
Volpi
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892.
Yasuhiro
Y
Yamazaki
Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M5S, Canada.
Patrick M
PM
Brauer
Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Ellen
E
van Rooijen
Division of Respiratory Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Atsuko
A
Hayashida
Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143.
Anne
A
Slavotinek
Department of Laboratory Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, 20892.
Hye
H
Sun Kuehn
Unit of Rare Diseases, Department of Pediatrics, Istituto Giannina Gaslini, 16148 Genoa, Italy.
Maja
M
Di Rocco
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1015 Lausanne, Switzerland.
Carlo
0000-0002-0733-9950
C
Rivolta
San Raffaele Telethon Institute for Gene Therapy, Istituto di Ricerca e Cura a Carattere Scientifico San Raffaele Scientific Institute, 20132 Milan, Italy.|Consiglio Nazionale delle Ricerche-Istituto di Ricerca Genetica e Biomedica, Milan Unit, 20138 Milan, Italy.
Ileana
0000-0002-2592-1274
I
Bortolomai
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Likun
L
Du
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Kerstin
K
Felgentreff
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Lisa
L
Ott de Bruin
Division of Respiratory Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Kazutaka
K
Hayashida
Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143.
George
G
Freedman
San Raffaele Telethon Institute for Gene Therapy, Istituto di Ricerca e Cura a Carattere Scientifico San Raffaele Scientific Institute, 20132 Milan, Italy.
Genni Enza
0000-0002-4994-1595
GE
Marcovecchio
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Kelly
0000-0001-5732-6405
K
Capuder
Tata Consultancy Services Innovation Labs, Telangana 500081, India.
Prisni
0000-0002-6080-6079
P
Rath
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Nicole
0000-0003-2571-0984
N
Luche
Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Elliott J
EJ
Hagedorn
Unita' Operativa Pediatria 2, Istituto Giannina Gaslini, 16148 Genoa, Italy.
Antonella
A
Buoncompagni
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1015 Lausanne, Switzerland.|Division of Genetic Medicine, Lausanne University Hospital, University of Lausanne, 1015 Lausanne, Switzerland.
Beryl
B
Royer-Bertrand
A. Nocivelli Institute for Molecular Medicine, University of Brescia, 25123 Brescia, Italy.
Silvia
0000-0001-8137-4642
S
Giliani
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Pietro Luigi
PL
Poliani
Centro di ricerca emato-oncologica AIL, Spedali Civili, 25123 Brescia, Italy.
Luisa
L
Imberti
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892.
Kerry
0000-0002-3432-3137
K
Dobbs
Department of Biological Sciences, University of South Carolina, Columbia, SC 29208.
Fabienne E
0000-0002-7867-748X
FE
Poulain
Unita' Operativa Pediatria 2, Istituto Giannina Gaslini, 16148 Genoa, Italy.
Alberto
0000-0001-7642-1459
A
Martini
Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
John
J
Manis
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180.
Robert J
RJ
Linhardt
San Raffaele Telethon Institute for Gene Therapy, Istituto di Ricerca e Cura a Carattere Scientifico San Raffaele Scientific Institute, 20132 Milan, Italy.
Marita
M
Bosticardo
Department of Laboratory Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, 20892.
Sergio Damian
SD
Rosenzweig
Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
Hane
H
Lee
Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143.
Jennifer M
0000-0001-6623-6276
JM
Puck
Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M5S, Canada.
Juan Carlos
0000-0003-2538-3178
JC
Zúñiga-Pflücker
Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Leonard
0000-0003-0860-926X
L
Zon
Division of Respiratory Diseases, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Pyong Woo
0000-0002-7979-4979
PW
Park
Division of Genetic Medicine, Lausanne University Hospital, University of Lausanne, 1015 Lausanne, Switzerland luigi.notarangelo2@nih.gov asuperti@unil.ch.
Andrea
0000-0002-3543-7531
A
Superti-Furga
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892 luigi.notarangelo2@nih.gov asuperti@unil.ch.
Luigi D
0000-0002-8335-0262
LD
Notarangelo
D000818:Animals; D001848:Bone Diseases, Developmental / Q000209:etiology*; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000209:etiology*; D005260:Female; D006497:Heparan Sulfate / Q000502:physiology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D007223:Infant; D008214:Lymphocytes / Q000502:physiology; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D015027:Zebrafish
D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; C110774:EXTL3 protein, human