title: Deletion of the Snord116/SNORD116 Alters Sleep in Mice and Patients with Prader-Willi Syndrome.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neuroscience and Brain Technologies (NBT) Department, Istituto Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova (Italy).
authors.forename: Glenda
authors.initials: G
authors.lastname: Lassi
authors.affiliation: Department of Neurology and Neurorehabilitation, S. Giuseppe Hospital, IRCCS Istituto Auxologico Italiano, Piancavallo (VB), Italy. Department of Neurosciences, University of Turin, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Priano
authors.affiliation: Neuroscience and Brain Technologies (NBT) Department, Istituto Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova (Italy).
authors.forename: Silvia
authors.initials: S
authors.lastname: Maggi
authors.affiliation: Neuroscience and Brain Technologies (NBT) Department, Istituto Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova (Italy).
authors.forename: Celina
authors.initials: C
authors.lastname: Garcia-Garcia
authors.affiliation: Neuroscience and Brain Technologies (NBT) Department, Istituto Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova (Italy).
authors.forename: Edoardo
authors.initials: E
authors.lastname: Balzani
authors.affiliation: Department of Neurology and Neurorehabilitation, S. Giuseppe Hospital, IRCCS Istituto Auxologico Italiano, Piancavallo (VB), Italy. Department of Neurosciences, University of Turin, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: El-Assawy
authors.affiliation: Istituto Italiano di Tecnologia. Center for Neuroscience and Cognitive Systems, Rovereto, Italy.|Center for Mind and Brain Sciences, University of Trento, Rovereto, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pagani
authors.affiliation: Neuroscience and Brain Technologies (NBT) Department, Istituto Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova (Italy).
authors.forename: Federico
authors.initials: F
authors.lastname: Tinarelli
authors.affiliation: Laboratory of Medical Cytogenetics, Istituto Auxologico Italiano, Cusano Milanino (MI), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giardino
authors.affiliation: Department of Neurology and Neurorehabilitation, S. Giuseppe Hospital, IRCCS Istituto Auxologico Italiano, Piancavallo (VB), Italy. Department of Neurosciences, University of Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauro
authors.affiliation: MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Peters
authors.affiliation: Istituto Italiano di Tecnologia. Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzi
authors.affiliation: Division of Auxology, S. Giuseppe Hospital, Research Institute, Istituto Auxologico Italiano, Piancavallo di Oggebbio (VB), Verbania, Italy.
authors.forename: Graziano
authors.initials: G
authors.lastname: Grugni
authors.affiliation: Neuroscience and Brain Technologies (NBT) Department, Istituto Italiano di Tecnologia (IIT), via Morego 30, 16163 Genova (Italy).
authors.forename: Valter
authors.initials: V
authors.lastname: Tucci
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000235:genetics; D015331:Cohort Studies; D004569:Electroencephalography; D005260:Female; D005838:Genotype; D066128:Gray Matter / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D009765:Obesity / Q000503:physiopathology; D000072740:Paternal Inheritance / Q000235:genetics; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000503:physiopathology*; D020537:RNA, Small Nucleolar / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D012890:Sleep / Q000235:genetics*; D012895:Sleep, REM / Q000235:genetics; D013826:Theta Rhythm
chemical_list: D020537:RNA, Small Nucleolar; C000601579:SNORD116 RNA, human; C000609194:SNORD116 RNA, mouse
keywords: Prader-Willi; Snord116; sleep; temperature; theta rhythms