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
N1 - Publisher Copyright:
© 2017 Volpi et al.
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 -