Human Molecular Genetics Advance Access published online on June 4, 2009
Human Molecular Genetics, 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, 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: Dr. I. Sadaf Farooqi – Tel: +44 1223 762 634; Fax = +44 1223 762 657; Email = isf20{at}cam.ac.uk, Dr. Alexandra I.F. Blakemore – Tel: +44 207 594 6511; Fax = +44 207 594 6543; Email = a.blakemore{at}imperial.ac.uk
Received March 31, 2009; Revised June 1, 2009; Accepted June 1, 2009
Objective: 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.
Research Design and Methods: 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 hybridisation (aCGH) and Affymetrix 6.0 genotyping arrays. The identified deletion was validated using multiplex ligation-dependent probe amplification (MLPA) and long range PCR, followed by breakpoint sequencing which enabled precise localisation of the deletion.
Results: We identified a 
187kb 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. Characterisation 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.
Conclusions: 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-q13, a region that includes multiple protein-coding genes as well as several noncoding snoRNAs. These findings provide direct evidence for the role of a particular family of noncoding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth and reproduction.
These authors contributed equally to this work.
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