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.

In this study we identify a novel role of SNORD116/Snord116 in sleep disturbance in Prader-Willi syndrome (PWS). We observed abnormalities in REM sleep both in patients with PWS and in a mouse model of the syndrome, which lacks Snord116. We detected hippocampal alterations in mice that are in agreement with the functional deficit in sleep. PWS is caused by genomic imprinting defects; therefore our findings promote a significant new perspective in the investigation of sleep. This new work, along with previous evidence of parent-of-origin effects on sleep, provides support for a significant role of genomic imprinting in sleep regulatory mechanisms.