CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
Diabetes. 2010 Jan;59(1):311-8. doi: 10.2337/db09-0703. Epub 2009 Oct 15.
Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass- and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto(-/-) mice are lean and Fto(+/-) mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO.
We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants.
We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals.
Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme.
脂肪量和肥胖相关基因（FTO）内含子 1 中的单核苷酸多态性（SNPs）与人肥胖密切相关，而 Fto(-/-)小鼠消瘦，Fto(+/-)小鼠对饮食诱导的肥胖具有抗性。我们旨在确定 FTO 突变是否在消瘦或肥胖人群中不成比例地存在，并利用这些突变来理解 FTO 内的结构-功能关系。
我们对 1433 名严重肥胖者和 1433 名消瘦者的 FTO 所有编码外显子进行测序。我们研究了选定的非同义变体的酶活性。
我们在消瘦者（2.3%）和肥胖者（2.4%）中发现了 33 个杂合非同义变体，其中 8 个突变仅存在于肥胖者中，11 个仅存在于消瘦者中。两个新的突变取代了绝对保守的残基：催化结构域中的 R322Q 和预测的底物识别盖中的 R96H。R322Q 不能在 3-甲基胸苷存在或不存在的情况下催化 2-氧戊二酸转化为琥珀酸。R96H 保留了一些基础活性，但 3-甲基胸苷不能增强其活性。然而，两者都存在于消瘦者和肥胖者中。
FTO 存在杂合、失功能突变，但在消瘦者和肥胖者中均有发现。尽管内含子 1 SNPs 在多个群体中与肥胖明确相关，并且鼠类研究强烈表明 FTO 在能量平衡中起作用，但人类中一个功能性 FTO 拷贝的缺失似乎与消瘦或肥胖都相容。对 FTO 突变的功能分析为该酶的结构-功能关系提供了新的见解。
