Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer
Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer
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DOI：
10.1086/386293
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发表时间：
2004-05-01
影响因子：
9.8
通讯作者：
Nieminen, P
中科院分区：
文献类型：
--
作者：
Lammi, L;Arte, S;Nieminen, P
Wnt信号调节大多数器官的胚胎模式形成和形态发生。Wnt信号调节的异常可能导致癌症。在此，我们利用定位克隆技术在一个芬兰家族中鉴定出致病突变，该家族中严重的恒牙缺失（少牙畸形）和结直肠肿瘤呈显性遗传分离。该家族中有11名成员至少缺失8颗恒牙，其中2人仅长出3颗恒牙。在8名少牙畸形患者中发现了不同类型的结直肠癌或癌前病变。我们表明少牙畸形和癌症易感性是由Wnt信号调节因子AXIN2中的无义突变Arg656Stop引起的。此外，我们在一名无亲缘关系的严重牙齿缺失的年轻患者中鉴定出AXIN2基因的一个新生移码突变1994 - 1995insG。这两种突变都可能激活Wnt信号。这些结果首次证明了Wnt信号对人类牙齿发育的重要性，并表明对Wnt信号活性的精细控制对于正常牙齿发育是必要的，因为Wnt信号的抑制和刺激都可能导致牙齿缺失。我们的研究结果引入了一个遗传性结直肠癌的新基因，并表明牙齿缺失可能是癌症易感性的一个指标。
Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis ( oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility.