Human Molecular Genetics Advance Access originally published online on June 4, 2009
Human Molecular Genetics 2009 18(17):3257-3265; doi:10.1093/hmg/ddp263
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A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism
1 Section of Genomic Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK 2 University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK 3 Department of Epidemiology & Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, UK 4 North West Thames Regional Genetics Service, NWLH NHS Trust, Watford Road, Harrow, UK 5 Department of Medical Genetics, University Medical Centre, Utrecht, The Netherlands 6 School of Human Sciences, Faculty of Life Science, London Metropolitan University, London, UK 7 Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK 8 CNRS 8090-Institute of Biology, Pasteur Institute, Lille, FR
* To whom correspondence should be addressed. Tel: +44 1223 762 634; Fax: +44 1223 762 657; Email: isf20{at}cam.ac.uk (I.S.F.); Tel: +44 207 594 6511; Fax: +44 207 594 6543; Email: a.blakemore{at}imperial.ac.uk (A.I.F.B.)
Received March 31, 2009; Accepted June 1, 2009
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 
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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