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INTRODUCTION: A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder clinically characterized by endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of the oxytocin (OXT) on it, have never been investigated in human neurons. METHODS: We studied the methylation marks in induced pluripotent stem-derived dopaminergic neurons carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neuron differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from the iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in these iPSC-derived dopaminergic neurons differentiated with or without OXT. RESULTS: The analysis revealed that 153,826 cytosines were differentially methylated between SNORD116 MD neurons and control neurons. Among the differentially methylated genes, we determined a list of genes also differentially expressed. Enrichment analysis of this list encompassed the dopaminergic system with COMT and SLC6A3. COMT displayed hypermethylation and under-expression in SNORD116 MD, and SLC6A3 displayed hypomethylation and over-expression in SNORD116 MD. RT-qPCR confirmed significant over-expression of SLC6A3 in SNORD116 MD neurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation. CONCLUSION: SNORD116 MD dopaminergic neurons displayed differential methylation and expression in the COMT and SLC6A3 genes, which are related to dopaminergic clearance.
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Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.