EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.
J Exp Med
; 214(3): 623-637, 2017 03 06.
Article
em En
| MEDLINE
| ID: mdl-28148688
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(rag2green 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças do Desenvolvimento Ósseo
/
Deficiências do Desenvolvimento
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N-Acetilglucosaminiltransferases
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Síndromes de Imunodeficiência
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Child, preschool
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Female
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Humans
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Infant
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article