Obesity associated with a mutation in a genetic regulator of adipocyte differentiation
Obesity associated with a mutation in a genetic regulator of adipocyte differentiation
复制标题
DOI：
10.1056/nejm199810013391403
复制
发表时间：
1998-10-01
影响因子：
158.5
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Ristow, M;Müller-Wieland, D;Kahn, CR
背景越来越多的证据表明遗传因素导致肥胖，但涉及的确切基因尚未确定。过氧化物酶体增殖物激活受体γ 2（过氧化物酶体增殖物激活受体γ 2）是一种转录因子，在脂肪细胞分化中起关键作用，因此该因子的基因突变可能使人易患肥胖症。包括121名肥胖受试者（定义为体重指数（体重（千克）除以身高（米）的平方）大于29）。我们评估了这些受试者的突变基因的过氧化物酶体增殖物激活受体γ 2的丝氨酸磷酸化位点或附近的位置114，负调控的蛋白质的转录活性，使用聚合酶链反应为基础的测定加上特定的内切酶消化。通过逆转录病毒转染和过度表达在小鼠fibroblasts.Results的突变的活性进行了分析，121肥胖的受试者中有4个有一个错义突变的基因为PPAR γ 2，导致脯氨酸转换为谷氨酰胺在位置115，相比，没有237例正常体重的受试者（P=0.01）。所有携带突变等位基因的受试者都明显肥胖，体重指数范围为37.9至47.3，而其他肥胖受试者的平均体重指数为33.6。突变基因在鼠成纤维细胞中的过表达导致产生一种蛋白质，其中114位丝氨酸的磷酸化是有缺陷的，以及加速细胞分化为脂肪细胞和比野生型PPAR γ 2更大的甘油三酯细胞积累。这些影响是类似的体外突变直接创建在Ser 114磷酸化site.Conclusions的Pro 115 Gln突变的PPAR γ 2加速脂肪细胞的分化，并可能导致肥胖。（N Engl J Med 1998;339：953-9.）（C）1998年，马萨诸塞州医学会。
Background There is increasing evidence of genetic factors leading to obesity, but the exact genes involved have not been defined. Peroxisome-proliferator-activated receptor gamma 2 (PPAR gamma 2) is a transcription factor that has a key role in adipocyte differentiation, and therefore mutations of the gene for this factor might predispose people to obesity.Methods We studied 358 unrelated German subjects, including 121 obese subjects (defined as those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of more than 29). We evaluated these subjects for mutations in the gene for PPAR gamma 2 at or near a site of serine phosphorylation at position 114 that negatively regulates the transcriptional activity of the protein, using a polymerase-chain-reaction-based assay coupled with specific endonuclease digestion. The activity of the mutation identified was analyzed by retroviral transfection and overexpression in murine fibroblasts.Results Four of the 121 obese subjects had a missense mutation in the gene for PPAR gamma 2 that resulted in the conversion of proline to glutamine at position 115, as compared with none of the 237 subjects of normal weight (P=0.01). All the subjects with the mutant allele were markedly obese, with body-mass-index values ranging from 37.9 to 47.3, as compared with a mean of 33.6 in the other obese subjects. Overexpression of the mutant gene in murine fibroblasts led to the production of a protein in which the phosphorylation of serine at position 114 was defective, as well as to accelerated differentiation of the cells into adipocytes and greater cellular accumulation of triglyceride than with the wild-type PPAR gamma 2. These effects were similar to those of an in vitro mutation created directly at the Ser114 phosphorylation site.Conclusions A Pro115Gln mutation in PPAR gamma 2 accelerates the differentiation of adipocytes and may cause obesity. (N Engl J Med 1998;339:953-9.) (C)1998, Massachusetts Medical Society.