SINGLE MISSENSE MUTATION IN THE TYROSINE KINASE CATALYTIC DOMAIN OF THE RET PROTOONCOGENE IS ASSOCIATED WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2B
SINGLE MISSENSE MUTATION IN THE TYROSINE KINASE CATALYTIC DOMAIN OF THE RET PROTOONCOGENE IS ASSOCIATED WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2B
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DOI：
10.1073/pnas.91.4.1579
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发表时间：
1994-02-15
影响因子：
11.1
通讯作者：
DONISKELLER, H
中科院分区：
文献类型：
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作者：
CARLSON, KM;DOU, SS;DONISKELLER, H
多发性内分泌瘤2B型（MEN 2B）是一种人类癌症综合征，其特征为甲状腺髓样癌（MTC）、嗜铬细胞瘤、粘膜神经瘤、肠道神经节细胞瘤以及骨骼和眼部异常。它既是一种遗传性疾病，也是一种新生疾病。对MEN 2B患者生殖系DNA的序列分析显示，在34个无关个体中存在RET原癌基因的相同点突变。在93名未受影响的个体中没有观察到这种序列差异，包括14名新生MEN 2B患者的正常父母。突变（ATG -> ACG）导致酪氨酸激酶结构域的催化核心区域内的蛋氨酸被苏氨酸取代。我们建议，这种氨基酸替换的影响底物相互作用，并导致显性致癌活性的RET蛋白。RET原癌基因细胞外配体结合结构域的错义突变先前已与观察到MTC的其他两种疾病[MEN 2A和家族性MTC（FMTC）]相关。MEN 2B代表已知是RET等位基因的第三种形式的可遗传MTC。推定受体蛋白质酪氨酸激酶的两个不同功能结构域的改变与MTC的发生有关。
Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals. This sequence difference was not observed in 93 unaffected individuals, including the normal parents of 14 de novo MEN 2B patients. The mutation (ATG --> ACG) results in the replacement of methionine with threonine within the catalytic core region of the tyrosine kinase domain. We propose that this amino acid replacement effects substrate interactions and results in dominant oncogenic activity by the RET protein. Missense mutations in the extracellular ligand-binding domain of the RET protooncogene previously have been associated with two other disorders [MEN 2A and familial MTC (FMTC)] in which MTC is observed. MEN 2B represents the third form of heritable MTC known to be an allele of RET. Alterations in two different functional domains of the putative receptor protein tyrosine kinase are implicated in development of MTC.