肥胖癥是一種具有高度遺傳性的疾病,，但迄今所報(bào)告的遺傳關(guān)聯(lián)性只能解釋身體質(zhì)量指數(shù)遺傳變化的很小一部分,。兩個(gè)小組報(bào)告了染色體16p11.2上所發(fā)生的基因刪除，它們也許可解釋所謂“高外顯率”突變中部分“缺失的遺傳性”,。這類突變很罕見,，但一旦存在，就會(huì)以非常高的頻率被與嚴(yán)重肥胖癥聯(lián)系起來(lái),。這跟與臨床癥候聯(lián)系不是很密切的更為常見的基因缺陷形成對(duì)比,。
Bochukova等人在300個(gè)患有嚴(yán)重早發(fā)性肥胖周的患者身上發(fā)現(xiàn)了罕見的復(fù)發(fā)性版本數(shù)突變體，它們是由涉及包括SH2B1（已知參與“萊普亭”和胰島素的信號(hào)作用）在內(nèi)的幾種基因的刪除造成的,。這些患者很多還患有神經(jīng)發(fā)育癥,。Walters等人在31個(gè)患有一種以前未被識(shí)別出的極端肥胖癥的患者的染色體16p11.2上識(shí)別出至少593個(gè)千堿基對(duì)的刪除。他們用來(lái)識(shí)別病灶的策略（利用數(shù)量較少的,、表現(xiàn)型較好的極端表現(xiàn)型人群進(jìn)行研究,，繼之以定向全基因組關(guān)聯(lián)研究和“population cohort”研究）有望作為一種手段，來(lái)識(shí)別更具普遍性的復(fù)雜代謝疾病中“缺失的遺傳性”,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 463, 666-670 (4 February 2010) | doi:10.1038/nature08689
Large, rare chromosomal deletions associated with severe early-onset obesity
Elena G. Bochukova1,5, Ni Huang2,5, Julia Keogh1, Elana Henning1, Carolin Purmann1, Kasia Blaszczyk1, Sadia Saeed1, Julian Hamilton-Shield3, Jill Clayton-Smith4, Stephen O’Rahilly1, Matthew E. Hurles2 & I. Sadaf Farooqi1
1 University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
2 Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
3 Bristol Children’s Hospital, Bristol BS2 8BG, UK
4 Genetic Medicine, St Mary’s Hospital, Oxford Road, Manchester M13 9WL, UK
5 These authors contributed equally to this work.
Obesity is a highly heritable and genetically heterogeneous disorder1. Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500?kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls (P?<?0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls (P?<?5?×?10-5). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism2, 3, 4 and mental retardation5; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signalling6. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity.
