Prevalence of loss-of-function FTO mutations in lean and obese individuals.
Prevalence of loss-of-function FTO mutations in lean and obese individuals.
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作者：
Meyre D;Proulx K;Kawagoe-Takaki H;Vatin V;Gutiérrez-Aguilar R;Lyon D;Ma M;Choquet H;Horber F;Van Hul W;Van Gaal L;Balkau B;Visvikis-Siest S;Pattou F;Farooqi IS;Saudek V;O'Rahilly S;Froguel P;Sedgwick B;Yeo GS
脂肪量和肥胖相关基因（FTO）内含子1中的单核苷酸多态性（SNP）与人类肥胖密切相关，而Fto−/−小鼠是瘦的，Fto+/−小鼠对饮食诱导的肥胖有抵抗力。我们的目的是确定FTO突变是否在瘦或肥胖人群中不成比例地存在，并利用这些突变来了解FTO内的结构-功能关系。我们对1，433名严重肥胖和1，433名瘦个体的FTO所有编码外显子进行了测序。我们研究了选定的非同义变体的酶活性。我们确定了33个杂合非同义变异瘦（2.3%）和35个肥胖（2.4%）的个人，8个突变独特的肥胖和11个独特的瘦。两个新的突变取代绝对保守的残基：催化结构域中的R322 Q和预测的底物识别盖中的R96 H。在存在或不存在3-甲基胸苷的情况下，R322 Q不能催化2-酮戊二酸转化为琥珀酸。R96 H保留了一定的基础活性，3-甲基胸苷不能增强这种活性。然而，这两种情况都出现在瘦和肥胖的个体中。FTO中存在杂合的功能丧失突变，但在瘦和肥胖受试者中均发现。尽管内含子1 SNP在多个人群中与肥胖明确相关，并且鼠类研究强烈表明FTO在能量平衡中具有作用，但似乎人类中FTO的一个功能性拷贝的丢失与瘦或肥胖是相容的。对FTO突变的功能分析为这种酶的结构-功能关系提供了新的见解。
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.