Journal
GENETICS IN MEDICINE
Volume 23, Issue 9, Pages 1664-1672Publisher
SPRINGERNATURE
DOI: 10.1038/s41436-021-01185-y
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Funding
- French government's National Program for Clinical Research (PHRC) [NCT01298180]
- Clinical Research Program of Midi-Pyrenees [09004797]
- Pfizer [08766A10]
- Sandoz France
- IPSEN Beaufour [121176A10]
- Lilly [141641A10]
- French association for Prader-Willi Syndrome [R15062BB]
- Deutsche Forschungsgemeinschaft [RO5622/1-1, SK259/2-1]
- NIH [DK52431]
- Societe Francaise d'Endocrinologie et de Diabetologie Pediatrique (SFEDP)
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The study found elevated levels of IGFBP7 in PWS patients, which normalized under growth hormone therapy. Elevated levels of IGFBP7 were also found in Snord116 knockout mice and iPSC-derived neurons from SNORD116-deleted PWS patients. The findings suggest that SNORD116 deletion affects IGFBP7 levels and that modulation of IGFBP7 levels has implications in the management of PWS under growth hormone therapy.
PURPOSE: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction due to deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene appears critical for the expression of the PWS phenotype. We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy (GHT), the main approved treatment for PWS. METHODS: We collected serum and induced pluripotent stem cells (iPSCs) from GH-treated PWS patients to differentiate into dopaminergic neurons, and in parallel used a Snord116 knockout mouse model. We analyzed the expression of factors potentially linked to GH responsiveness. RESULTS: We found elevated levels of circulating IGFBP7 in naive PWS patients, with IGFBP7 levels normalizing under GHT. We found elevated IGFBP7 levels in the brains of Snord116 knockout mice and in iPSC-derived neurons from a SNORD116-deleted PWS patient. High circulating levels of IGFBP7 in PWS patients may result from both increased IGFBP7 expression and decreased IGFBP7 cleavage, by downregulation of the proconvertase PC1. CONCLUSION: SNORD116 deletion affects IGFBP7 levels, while IGFBP7 decreases under GHT in PWS patients. Modulation of the IGFBP7 level, which interacts with IGF1, has implications in the pathophysiology and management of PWS under GHT.
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