A novel germline mutation in Peroxisome Proliferator-Activated Receptor γ gene associated with large intestine polyp formation and dyslipidemia
A novel germline mutation in Peroxisome Proliferator-Activated Receptor γ gene associated with large intestine polyp formation and dyslipidemia
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DOI：
10.1016/j.bbadis.2010.01.012
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发表时间：
2010-06-01
影响因子：
6.2
通讯作者：
Colantuoni, V.
中科院分区：
文献类型：
--
作者：
Capaccio, D.;Ciccodicola, A.;Colantuoni, V.
我们报道了一个新的PPARG胚系突变，该突变发生在一个受结直肠癌影响的患者身上，该突变用成熟蛋白(S289C)中的半胱氨酸取代了丝氨酸289。该突变体的反式激活能力受损，对野生型受体呈显性负性。此外，它不再抑制细胞在体外和体内的增殖。有趣的是，S289C突变体不能很好地激活靶基因，并干扰肿瘤组织和近端正常黏膜的炎症途径。一直以来，只有突变携带者才会表现出可能演变为发育不良息肉的结肠病变。先证者还表现为血脂异常、高血压和超重，与2型糖尿病无关：值得注意的是，家族成员的突变检测呈阳性，仅表现出不同外显率的血脂异常，其他生化指标在正常范围内。最后，将突变叠加到配体结合域的晶体结构上，新的Cys289变得与Cys285位置如此接近，形成了S-S桥。这将减少配体结合口袋的深度，阻碍激动剂的定位，解释突变蛋白的生物学效应和亚细胞分布。这是第一例与高脂血症和结肠息肉形成相关的PPARG胚系突变，可进展为全面的腺癌。(C)2010爱思唯尔B.V.保留所有权利。
We report a novel PPARG germline mutation in a patient affected by colorectal cancer that replaces serine 289 with cysteine in the mature protein (S289C). The mutant has impaired transactivation potential and acts as dominant negative to the wild type receptor. In addition, it no longer restrains cell proliferation both in vitro and in vivo. Interestingly, the S289C mutant poorly activates target genes and interferes with the inflammatory pathway in tumor tissues and proximal normal mucosa. Consistently, only mutation carriers exhibit colonic lesions that can evolve to dysplastic polyps. The proband presented also dyslipidemia, hypertension and overweight, not associated to type 2 diabetes: of note, family members tested positive for the mutation and display only a dyslipidemic profile at variable penetrance with other biochemical parameters in the normal range. Finally, superimposing the mutation to the crystal structure of the ligand binding domain, the new Cys289 becomes so closely positioned to Cys285 to form an S-S bridge. This would reduce the depth of the ligand binding pocket and impede agonist positioning, explaining the biological effects and subcellular distribution of the mutant protein. This is the first PPARG germline mutation associated with dyslipidemia and colonic polyp formation that can progress to full-blown adenocarcinoma. (C) 2010 Elsevier B.V. All rights reserved.