Article ; Online: An in vivo functional assay to characterize human STAT5B genetic variants during zebrafish development.
2023 Volume 32, Issue 15, Page(s) 2473–2484
Abstract: Growth hormone (GH) binding to GH receptor activates janus kinase 2 (JAK2)-signal transducer and activator of transcription 5b (STAT5b) pathway, which stimulates transcription of insulin-like growth factor-1 (IGF1), insulin-like growth factor binding ... ...
| Abstract | Growth hormone (GH) binding to GH receptor activates janus kinase 2 (JAK2)-signal transducer and activator of transcription 5b (STAT5b) pathway, which stimulates transcription of insulin-like growth factor-1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3) and insulin-like growth factor acid-labile subunit (IGFALS). Although STAT5B deficiency was established as an autosomal recessive disorder, heterozygous dominant-negative STAT5B variants have been reported in patients with less severe growth deficit and milder immune dysfunction. We developed an in vivo functional assay in zebrafish to characterize the pathogenicity of three human STAT5B variants (p.Ala630Pro, p.Gln474Arg and p.Lys632Asn). Overexpression of human wild-type (WT) STAT5B mRNA and its variants led to a significant reduction of body length together with developmental malformations in zebrafish embryos. Overexpression of p.Ala630Pro, p.Gln474Arg or p.Lys632Asn led to an increased number of embryos with pericardial edema, cyclopia and bent spine compared with WT STAT5B. Although co-injection of WT and p.Gln474Arg and WT and p.Lys632Asn STAT5B mRNA in zebrafish embryos partially or fully rescues the length and the developmental malformations in zebrafish embryos, co-injection of WT and p.Ala630Pro STAT5B mRNA leads to a greater number of embryos with developmental malformations and a reduction in body length of these embryos. These results suggest that these variants could interfere with endogenous stat5.1 signaling through different mechanisms. In situ hybridization of zebrafish embryos overexpressing p.Gln474Arg and p.Lys632Asn STAT5B mRNA shows a reduction in igf1 expression. In conclusion, our study reveals the pathogenicity of the STAT5B variants studied. |
|---|---|
| MeSH term(s) | Animals ; Humans ; Zebrafish/genetics ; Zebrafish/metabolism ; STAT5 Transcription Factor/genetics ; STAT5 Transcription Factor/metabolism ; Growth Hormone ; Signal Transduction/genetics ; RNA, Messenger ; Insulin-Like Growth Factor I/genetics |
| Chemical Substances | STAT5 Transcription Factor ; Growth Hormone (9002-72-6) ; RNA, Messenger ; Insulin-Like Growth Factor I (67763-96-6) ; STAT5B protein, human |
| Language | English |
| Publishing date | 2023-04-24 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1108742-0 |
| ISSN | 1460-2083 ; 0964-6906 |
| ISSN (online) | 1460-2083 |
| ISSN | 0964-6906 |
| DOI | 10.1093/hmg/ddad078 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 3469: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.