Deletion of theSnord116/SNORD116Alters Sleep in Mice and Patients with Prader-Willi Syndrome

• DOI: 10.5665/sleep.5542
• Publication Date: 2016-02-29T21:29:07Z
• Authors: Glenda Lassi; Lorenzo Priano; Silvia Maggi; Celina Garcia-Garcia; Edoardo Balzani; Nadia El-Assawy; Marco Pagani; Federico Tinarelli; Daniela Giardino; Alessandro Mauro; Jo Peters; Alessandro Gozzi; Graziano Grugni; Valter Tucci
• Keywords: Adult; Male; 0301 basic medicine; 570; Genotype; 610; Hippocampus; Cohort Studies; Mice; 03 medical and health sciences; Journal Article; Animals; Humans; RNA, Small Nucleolar; Prader-Willi; Snord116; sleep; temperature; theta rhythms; Obesity; Theta Rhythm; Gray Matter; Small Nucleolar; Sequence Deletion; Brain; Electroencephalography; Circadian Rhythm; REM; Case-Control Studies; Paternal Inheritance; RNA; Female; Sleep; Prader-Willi Syndrome

Sleep-wake disturbances are often reported in Prader-Willi syndrome (PWS), a rare neurodevelopmental syndrome that is associated with paternally-expressed genomic imprinting defects within the human chromosome region 15q11-13. One of the candidate genes, prevalently expressed in the brain, is the small nucleolar ribonucleic acid-116 (SNORD116). Here we conducted a translational study into the sleep abnormalities of PWS, testing the hypothesis that SNORD116 is responsible for sleep defects that characterize the syndrome.We studied sleep in mutant mice that carry a deletion of Snord116 at the orthologous locus (mouse chromosome 7) of the human PWS critical region (PWScr). In particular, we assessed EEG and temperature profiles, across 24-h, in PWScr (m+/p-) heterozygous mutants compared to wild-type littermates. High-resolution magnetic resonance imaging (MRI) was performed to explore morphoanatomical differences according to the genotype. Moreover, we complemented the mouse work by presenting two patients with a diagnosis of PWS and characterized by atypical small deletions of SNORD116. We compared the individual EEG parameters of patients with healthy subjects and with a cohort of obese subjects.By studying the mouse mutant line PWScr(m+/p-), we observed specific rapid eye movement (REM) sleep alterations including abnormal electroencephalograph (EEG) theta waves. Remarkably, we observed identical sleep/EEG defects in the two PWS cases. We report brain morphological abnormalities that are associated with the EEG alterations. In particular, mouse mutants have a bilateral reduction of the gray matter volume in the ventral hippocampus and in the septum areas, which are pivotal structures for maintaining theta rhythms throughout the brain. In PWScr(m+/p-) mice we also observed increased body temperature that is coherent with REM sleep alterations in mice and human patients.Our study indicates that paternally expressed Snord116 is involved in the 24-h regulation of sleep physiological measures, suggesting that it is a candidate gene for the sleep disturbances that most individuals with PWS experience.