title: A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism.
abstract: Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight in humans. We report a 19-year-old male with hyperphagia and severe obesity, mild learning difficulties and hypogonadism, in whom diagnostic tests for Prader-Willi syndrome (PWS) had been negative. We carried out detailed clinical and metabolic phenotyping of this patient and investigated the genetic basis of this obesity syndrome using Agilent 185 k array comparative genomic hybridization (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification and long-range PCR, followed by breakpoint sequencing which enabled precise localization of the deletion. We identified a approximately 187 kb microdeletion at chromosome 15q11-13 that encompasses non-coding small nucleolar RNAs (including HBII-85 snoRNAs) which were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism and growth failure. We have identified a novel deletion on chromosome 15q11-13 in an individual with hyperphagia, obesity, hypogonadism and other features associated with PWS, which is normally caused by deficiency of several paternally expressed imprinted transcripts within chromosome 15q11-13, a region that includes multiple protein-coding genes as well as several non-coding snoRNAs. These findings provide direct evidence for the role of a particular family of non-coding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction.
authors.affiliation: Section of Genomic Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: de Smith
authors.forename: Carolin
authors.initials: C
authors.lastname: Purmann
authors.forename: Robin G
authors.initials: RG
authors.lastname: Walters
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ellis
authors.forename: Susan E
authors.initials: SE
authors.lastname: Holder
authors.forename: Mieke M
authors.initials: MM
authors.lastname: Van Haelst
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.forename: Una L
authors.initials: UL
authors.lastname: Fairbrother
authors.forename: Mehul
authors.initials: M
authors.lastname: Dattani
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Elana
authors.initials: E
authors.lastname: Henning
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Alexandra I F
authors.initials: AI
authors.lastname: Blakemore
mesh_terms: D000595:Amino Acid Sequence; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D006801:Humans; D006963:Hyperphagia / Q000235:genetics* / Q000378:metabolism; D007006:Hypogonadism / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D020537:RNA, Small Nucleolar / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D020537:RNA, Small Nucleolar