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Updated: May 31, 2026
08:35
Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
Pharmacologic correction of dominant-negative GH1 deficiency causing mutations
Justin S Poling1, John A Phillips, Joy D Cogan
1Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Clinical and Translational Science
|June 29, 2011
Summary
Pharmaceuticals impact growth hormone gene (GH1) splicing in familial isolated growth hormone deficiency type II (IGHD II). Dexamethasone and digoxin increased the GH1 transcript ratio, potentially reducing disease severity, while other agents decreased it.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Familial isolated growth hormone deficiency type II (IGHD II) is caused by dominant-negative mutations in the growth hormone gene (GH1).
- The ratio of 17.5-/22-kDa GH1 transcripts correlates with IGHD II phenotype severity.
- Alternative splicing of the GH1 gene is a potential therapeutic target.
Purpose of the Study:
- To investigate the effect of pharmaceutical agents on the GH1 transcript ratio.
- To determine if modulating alternative splicing can alter the IGHD II phenotype.
Main Methods:
- Peripheral blood mononuclear cells from IGHD II patients and family members were treated with various pharmacologic agents.
- Real-time PCR was used to quantify the 17.5-/22-kDa GH1 transcript ratios.
Main Results:
- Dexamethasone and digoxin significantly increased the 17.5-/22-kDa GH1 transcript ratio.
- Sodium butyrate and 5-iodotubericidin significantly decreased the 17.5-/22-kDa GH1 transcript ratio.
Conclusions:
- Specific pharmaceutical agents can modulate GH1 alternative splicing.
- These findings suggest potential therapeutic strategies to reduce IGHD II severity or identify agents that may exacerbate the condition.
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