Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome associated psychosis

Abstract

Background: Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by a loss of usually paternally expressed, maternally imprinted genes located on chromosome 15q11-q13. Individuals with PWS display a specific behavioral phenotype and have a higher susceptibility than the general population for certain psychiatric conditions, especially psychosis. An impairment of the oxytocin system has been described in Prader-Willi syndrome, but has not yet been investigated on the epigenetic level. Recent studies have pointed out altered methylation patterns of the oxytocin receptor gene (OXTR) in various psychiatric disorders, including psychosis. Methods: In this study, we investigated methylation rates of CpG dinucleotides in the promoter region of the oxytocin receptor gene via bisulfite-sequencing using DNA extracted from peripheral blood samples of 31 individuals with PWS and 14 controls matched for age, sex and BMI. Results: Individuals with PWS show significantly lower methylation in the intron 1 region of the OXTR than neurotypical controls (p=0.012). Furthermore, male PWS subjects with psychosis show significantly lower methylation of the OXTR exon 1 region than those without psychosis (p=0.002). Transcription factor binding site analysis revealed E2F1 as a transcription factor potentially binding to the exon 1 region. E2F1 is physiologically regulated by Necdin, an anti-apoptotic protein whose corresponding gene is located within the PWS locus. Conclusion: This study provides evidence of a disruption of the Oxytocin system on an epigenetic level in PWS in general and in individuals with PWS and psychosis.

Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

“…However, given that OXT receptors in Magel2 KO mice are downregulated (24), it is likely that the increased activity results from homeostatic compensation. A similar compensation is seen in PWS patientswhile on one hand they report reduced methylation of OXT-receptor (25) and increased plasma OXT (26), treatment with OXT-receptor agonist improves symptoms of PWS in some clinical studies (27)(28)(29) (but not others (30)). Furthermore, spike broadening of OXT neurons as seen here is observed during lactation (31,32), suggesting that reduction of Ca 2+ spike duration observed in Magel2 KO mice reflects a physiologically relevant deficit.…”