Deletion of the Snord116/SNORD116 Alters Sleep in Mice and Patients with Prader-Willi Syndrome

• Published in: Sleep (New York, N.Y.) Vol. 39; no. 3; pp. 637 - 644
• Main Authors: Lassi, Glenda, Priano, Lorenzo, Maggi, Silvia, Garcia-Garcia, Celina, Balzani, Edoardo, El-Assawy, Nadia, Pagani, Marco, Tinarelli, Federico, Giardino, Daniela, Mauro, Alessandro, Peters, Jo, Gozzi, Alessandro, Grugni, Graziano, Tucci, Valter
• Format: Journal Article
• Language: English
• Published: United States Associated Professional Sleep Societies, LLC 01.03.2016
• Subjects: Adult; Animals; Basic Science; Brain - pathology; Brain - physiopathology; Case-Control Studies; Circadian Rhythm - genetics; Cohort Studies; Electroencephalography; Female; Genotype; Gray Matter - pathology; Gray Matter - physiopathology; Hippocampus - pathology; Hippocampus - physiopathology; Humans; Male; Mice; Obesity - physiopathology; Paternal Inheritance - genetics; Prader-Willi Syndrome - genetics; Prader-Willi Syndrome - physiopathology; RNA, Small Nucleolar - genetics; Sequence Deletion - genetics; Sleep - genetics; Sleep, REM - genetics; Theta Rhythm; sleep; temperature; Prader-Willi; Snord116; theta rhythms
• DOI: 10.5665/sleep.5542
• ISSN: 0161-8105

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.