SNORD116 and growth hormone therapy impact IGFBP7 in Prader-Willi syndrome

Area of Science:

• Genetics
• Neuroendocrinology
• Molecular Biology

Background:

• Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder characterized by hypothalamic dysfunction.
• Deficiency of imprinted genes on chromosome 15q11-q13, particularly the SNORD116 gene, is critical for the PWS phenotype.
• Growth hormone therapy (GHT) is the primary treatment for PWS, but its precise molecular mechanisms require further elucidation.

Purpose of the Study:

• To investigate the role of the SNORD116 gene in cellular and animal models of PWS.
• To clarify the impact of SNORD116 on growth hormone therapy (GHT) responsiveness.
• To identify molecular factors involved in PWS pathophysiology and GHT efficacy.

Main Methods:

• Collected serum and induced pluripotent stem cells (iPSCs) from GHT-treated PWS patients.
• Differentiated iPSCs into dopaminergic neurons for analysis.
• Utilized a Snord116 knockout mouse model to study gene function.
• Analyzed the expression of factors related to GH responsiveness, including IGFBP7 and PC1.

Main Results:

• Elevated circulating IGFBP7 levels were observed in naive PWS patients, which normalized with GHT.
• Increased IGFBP7 levels were detected in the brains of Snord116 knockout mice and in iPSC-derived neurons from PWS patients with SNORD116 deletion.
• High IGFBP7 levels in PWS may stem from increased expression and reduced cleavage due to PC1 downregulation.

Conclusions:

• SNORD116 deletion significantly impacts IGFBP7 levels in PWS.
• IGFBP7 levels decrease under GHT in PWS patients.
• Modulating IGFBP7, which interacts with IGF1, holds therapeutic implications for PWS pathophysiology and GHT management.