Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity
Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity
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DOI：
10.2337/diabetes.54.9.2663
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发表时间：
2005-09-01
期刊：
影响因子：
7.7
通讯作者：
Yanovski, JA
中科院分区：
文献类型：
--
作者：
Feng, NP;Young, SF;Yanovski, JA
人类连锁研究和MC3R敲除小鼠模型都表明MC3R可能在能量稳态中起重要作用。在这里，我们发现，在355超重和非超重儿童，8.2%的双纯合子的错义MC3R序列变异（Thr6Lys和Val81Ile）。与野生型或杂合子儿童相比，这些儿童明显更重（BMI和BMI SD评分：P <0.0001），有更多的体脂（体脂质量和脂肪质量百分比：P <0.001），血浆瘦素（P <0.0001）和胰岛素浓度（P <0.001）更高，胰岛素抵抗（P < 0.008）更大。这两种序列变异在非洲裔美国儿童中比高加索儿童更常见。体外表达研究发现，双突变MC3R部分失活，受体结合位点明显减少，信号转导减少，蛋白表达减少。我们的结论是，减少MC3R的表达在这个双MC3R变异可能是一个诱发因素过度体重增加的儿童。
Both human linkage studies and MC3R knockout mouse models suggest that the MC3R may play an important role in energy homeostasis. Here we show that among 355 overweight and nonoverweight children, 8.2% were double homozygous for a pair of missense MC3R sequence variants (Thr6Lys and Val81Ile). Such children were significantly heavier (BMI and BMI SD score: P < 0.0001), had more body fat (body fat mass and percentage fat mass: P < 0.001), and had greater plasma leptin (P < 0.0001) and insulin concentrations (P < 0.001) and greater insulin resistance (P < 0.008) than wild-type or heterozygous children. Both sequence variants were more common in African-American than Caucasian children. In vitro expression studies found the double mutant MC3R was partially inactive, with significantly fewer receptor binding sites, decreased signal transduction, and less protein expression. We conclude that diminished MC3R expression in this double MC3R variant may be a predisposing factor for excessive body weight gain in children.