Rescue of Isolated GH Deficiency Type II (IGHD II) via Pharmacologic Modulation of GH-1 Splicing

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Isolated GH deficiency (IGHD) type II results from GH-1 gene mutations affecting RNA splicing, producing a toxic 17.5-kDa GH isoform.
• This toxic isoform inhibits wild-type hGH accumulation and secretion, leading to pituitary damage and potential secondary hormonal deficiencies despite standard recombinant GH therapy.

Purpose of the Study:

• To investigate the potential of butyrate, a histone deacetylase inhibitor, to restore normal GH-1 splicing patterns.
• To evaluate if butyrate treatment can increase the production and secretion of the functional 22-kDa GH isoform in a cellular model of IGHD type II.

Main Methods:

• Rat pituitary cells expressing the human GHRH receptor (GC-GHRHR) were transfected with wild-type hGH and/or GH-1 splice site mutants.
• Cells were treated with butyrate, and changes in GH transcript levels, intracellular GH content, and GH secretion were measured.
• The role of alternative splicing factor/splicing factor 2 (ASF/SF2) was assessed through overexpression studies.

Main Results:

• Butyrate treatment significantly increased GH transcript levels, intracellular GH content, and GH secretion in cells expressing wt-hGH and GH-1 mutants.
• The beneficial effects of butyrate were associated with increased levels of full-length GH transcripts.
• Overexpression of ASF/SF2 mimicked the effect of butyrate, enhancing the production of the 22-kDa GH isoform.

Conclusions:

• Butyrate effectively modulates GH-1 splicing, promoting the production of the functional 22-kDa GH isoform.
• This splicing modulation represents a promising therapeutic strategy for IGHD type II, potentially mitigating the toxic effects of aberrant GH isoforms.
• Targeting GH-1 splicing offers a novel research avenue for treating GHD and preventing pituitary complications.