EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay
| Autor: | Beryl Royer-Bertrand, Fabienne E. Poulain, Pietro Luigi Poliani, Luigi D. Notarangelo, Ellen van Rooijen, Ileana Bortolomai, Hye Sun Kuehn, Elliott J. Hagedorn, Robert J. Linhardt, Leonard I. Zon, Luisa Imberti, Pyong Woo Park, Genni Enza Marcovecchio, Atsuko Hayashida, Anne Slavotinek, George Freedman, Kerry Dobbs, Stefano Volpi, Prisni Rath, Patrick M. Brauer, Yasuhiro Yamazaki, Maja Di Rocco, Alberto Martini, Kazutaka Hayashida, Kelly Capuder, Juan Carlos Zúñiga-Pflücker, Sergio D. Rosenzweig, Marita Bosticardo, John P. Manis, Silvia Giliani, Andrea Superti-Furga, Jennifer M. Puck, Carlo Rivolta, Kerstin Felgentreff, Lisa Ott de Bruin, Nicole Luche, Antonella Buoncompagni, Hane Lee, Likun Du |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Developmental Disabilities medicine.disease_cause Fibroblast growth factor Medical and Health Sciences chemistry.chemical_compound Immunology and Allergy 2.1 Biological and endogenous factors Developmental Animals Bone Diseases Developmental Child Preschool Female Heparitin Sulfate Humans Immunologic Deficiency Syndromes Induced Pluripotent Stem Cells Infant Lymphocytes N-Acetylglucosaminyltransferases Zebrafish Mutation Immunology Aetiology Induced pluripotent stem cell Child Research Articles Pediatric biology Stem Cell Research - Induced Pluripotent Stem Cell - Human Heparan sulfate 3. Good health Cell biology Stem Cell Research - Nonembryonic - Non-Human Bone Diseases 03 medical and health sciences Immune system Rare Diseases medicine Genetics Progenitor cell Preschool Stem Cell Research - Induced Pluripotent Stem Cell Brief Definitive Report medicine.disease biology.organism_classification Stem Cell Research Molecular biology 030104 developmental biology chemistry Dysplasia Congenital Structural Anomalies |
| Zdroj: | The Journal of experimental medicine, vol 214, iss 3 The Journal of experimental medicine, vol. 214, no. 3, pp. 623-637 The Journal of Experimental Medicine |
| Popis: | Volpi et al. demonstrate that hypomorphic EXTL3 mutations cause abnormalities of heparan sulfate composition, affect signaling in response to growth factors and cytokines, and perturb thymopoiesis, resulting in a novel genetic disease associating skeletal dysplasia, T cell immunodeficiency, and neurodevelopmental 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-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. |
| Databáze: | OpenAIRE |
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