Characterization of dominant-negative growth hormone receptor variants reveals a potential therapeutic target for short stature
| العنوان: | Characterization of dominant-negative growth hormone receptor variants reveals a potential therapeutic target for short stature |
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| المؤلفون: | Afiya Andrews, Emily Cottrell, Avinaash Maharaj, Tasneem Ladha, Jack Williams, Katharina Schilbach, Lena R Kaisinger, John R B Perry, Louise A Metherell, Peter J McCormick, Helen L Storr |
| المصدر: | European Journal of Endocrinology. 188:353-365 |
| بيانات النشر: | Oxford University Press (OUP), 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine |
| الوصف: | Objective Growth hormone insensitivity (GHI) encompasses growth restriction, normal/elevated growth hormone (GH), and low insulin-like growth factor I (IGF1). “Nonclassical” GHI is poorly characterized and is rarely caused by heterozygous dominant-negative (DN) variants located in the intracellular or transmembrane domains of the GH receptor (GHR). We sought to determine the molecular mechanisms underpinning the growth restriction in 2 GHI cases. Methods and Design A custom-made genetic investigative pipeline was exploited to identify the genetic cause of growth restriction in patients with GHI. Nanoluc binary technology (NanoBiT), in vitro splicing assays, western blotting, and flow cytometry, characterized the novel GHR variants. Results Novel heterozygous GHR variants were identified in 2 unrelated patients with GHI. In vitro splicing assays indicated both variants activated the same alternative splice acceptor site resulting in aberrant splicing and exclusion of 26 base pairs of GHR exon 9. The GHR variants produced truncated receptors and impaired GH-induced GHR signaling. NanoBiT complementation and flow cytometry showed increased cell surface expression of variant GHR homo/heterodimers compared to wild-type (WT) homodimers and increased recombinant human GH binding to variant GHR homo/heterodimers and GH binding protein (GHBP) cleaved from the variant GHRs. The findings demonstrated increased variant GHR dimers and GHBP with resultant GH sequestration. Conclusion We identified and characterized 2 novel, naturally occurring truncated GHR gene variants. Intriguingly, these DN GHR variants act via the same cryptic splice acceptor site, highlighting impairing GH binding to excess GHBP as a potential therapeutic approach. |
| تدمد: | 1479-683X 0804-4643 |
| DOI: | 10.1093/ejendo/lvad039 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::a2771ad904a4a923337dcf0a0b98b3c7 https://doi.org/10.1093/ejendo/lvad039 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........a2771ad904a4a923337dcf0a0b98b3c7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1479683X 08044643 |
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| DOI: | 10.1093/ejendo/lvad039 |