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

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

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

STUDY OBJECTIVES: 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.

Original languageEnglish
Pages (from-to)637-44
Number of pages8
JournalSleep
Volume39
Issue number3
DOIs
Publication statusPublished - 1 Mar 2016

Keywords

  • Adult
  • Animals
  • Brain
  • Case-Control Studies
  • Circadian Rhythm
  • Cohort Studies
  • Electroencephalography
  • Female
  • Genotype
  • Gray Matter
  • Hippocampus
  • Humans
  • Male
  • Mice
  • Obesity
  • Paternal Inheritance
  • Prader-Willi Syndrome
  • RNA, Small Nucleolar
  • Sequence Deletion
  • Sleep
  • Sleep, REM
  • Theta Rhythm
  • Journal Article

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