de Smith Adam J, Purmann Carolin, Walters Robin G, Ellis Richard J, Holder Susan E, Van Haelst Mieke M, Brady Angela F, Fairbrother Una L, Dattani Mehul, Keogh Julia M, Henning Elana, Yeo Giles S H, O'Rahilly Stephen, Froguel Philippe, Farooqi I Sadaf, Blakemore Alexandra I F
Section of Genomic Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
Hum Mol Genet. 2009 Sep 1;18(17):3257-65. doi: 10.1093/hmg/ddp263. Epub 2009 Jun 4.
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.
对严重早发性肥胖患者的基因研究，为调控人体体重的分子和生理途径提供了深入见解。我们报告了一名19岁男性，有食欲亢进和严重肥胖、轻度学习困难及性腺功能减退，其普拉德-威利综合征（PWS）诊断测试结果为阴性。我们对该患者进行了详细的临床和代谢表型分析，并使用安捷伦185 k阵列比较基因组杂交（aCGH）和Affymetrix 6.0基因分型阵列研究了这种肥胖综合征的遗传基础。使用多重连接依赖探针扩增和长程PCR验证了所鉴定的缺失，随后进行断点测序，从而能够精确确定缺失的定位。我们在15号染色体q11 - 13区域发现了一个约187 kb的微缺失，该区域包含非编码小核仁RNA（包括HBII - 85 snoRNAs），这些RNA在该患者的外周淋巴细胞中未表达。临床表型特征显示随意食物摄入量增加、调整无脂肪体重后的基础代谢率正常、部分促性腺激素缺乏性性腺功能减退和生长发育迟缓。我们在一名有食欲亢进、肥胖、性腺功能减退及其他与PWS相关特征的个体中，在15号染色体q11 - 13区域发现了一个新的缺失，PWS通常是由15号染色体q11 - 13区域内几个父源表达的印记转录本缺乏所致，该区域包括多个蛋白质编码基因以及几个非编码snoRNAs。这些发现为特定非编码RNA家族HBII - 85 snoRNA簇在人类能量稳态、生长和生殖中的作用提供了直接证据。
