1. SNORD116 and growth hormone therapy impact IGFBP7 in Prader–Willi syndrome
- Author
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Lisa Cole Burnett, Françoise Conte Auriol, Eric Bieth, Jean Pierre Salles, Juliette Salles, Maithé Tauber, Gwenaelle Diene, Catherine Molinas, Rudolph L. Leibel, Boris V. Skryabin, Isabelle Gennero, Timofey S. Rozhdestvensky, Sanaa Eddiry, Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence du Syndrome de Prader-Willi, Pôle Enfants [CHU Toulouse], Service Psychiatrie et psychologie médicale [CHU Toulouse], Pôle Psychiatrie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Illinois [Chicago] (UIC), University of Illinois System, Columbia University [New York], and Pistre, Karine
- Subjects
0301 basic medicine ,MESH: Prader-Willi Syndrome* / genetics ,medicine.medical_specialty ,MESH: RNA, Small Nucleolar ,congenital, hereditary, and neonatal diseases and abnormalities ,IGFBP7 ,[SDV]Life Sciences [q-bio] ,Induced Pluripotent Stem Cells ,MESH: Neurons ,MESH: Induced Pluripotent Stem Cells ,Article ,MESH: Prader-Willi Syndrome* / drug therapy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Neurodevelopmental disorder ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Small Nucleolar ,MESH: Animals ,MESH: Mice ,Genetics (clinical) ,Neurons ,MESH: Humans ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,business.industry ,Dopaminergic ,nutritional and metabolic diseases ,medicine.disease ,Phenotype ,Pathophysiology ,nervous system diseases ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Endocrinology ,MESH: Growth Hormone ,Growth Hormone ,Knockout mouse ,business ,Genomic imprinting ,Prader-Willi Syndrome ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; 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.
- Published
- 2021