Mutation of RET proto-oncogene in Families of multiple endocrine neoplasia type 2

多发性内分泌腺瘤2A和2B型（MEN 2A和2B）和家族性或散发性甲状腺髓样癌（MTC）与位于染色体10q11.2的RET原癌基因突变相关。我们调查了日本患者的RET突变谱（代表39个MEN2或FMTC家族和33个散发性MTCs）。在32例MEN2A患者中的31例和检查的所有3例FMTC患者中，发现编码RET蛋白胞外结构域中3个特异性半胱氨酸残基之一的核苷酸序列突变。在密码子918处的突变，导致蛋白质的酪氨酸激酶结构域中的苏氨酸取代甲硫氨酸，在所有4名MEN2B患者和33名散发性MTCs中的7名的生殖系DNA中发现。在两名散发性MTCs患者中检测到密码子768的种系突变，GAG至GAC（Glu至Asp）。我们还确定了两个新的体细胞突变在散发性MTCs，一个在密码子631（天冬氨酸甘氨酸）和其他密码子634（半胱氨酸精氨酸）。这两个突变将有助于研究RET蛋白的功能结构域。

Multiple endocrine neoplasia types 2A and 2B (MEN 2A and 2B) and familial or sporadic medullary thyroid carcinomas (MTC) are associated with mutations in the RET proto-oncogene located at chromosome 10q11.2. We investigated the spectrum of RET mutations among Japanese patlents with these diseased (representatives of 39 families with MEN2 or FMTC,and 33 sporadic MTCs). Mutations in nucleotide sequences encoding one of three specific cyteine residues in the extracellular domain of RET protein were found in 31 of the 32 MEN2A patients and all three FMTC patients examined. A mutation at codon 918, causing the substitution of threonine for methionine in the tyrosine kinase domain of the protein, was found in germline DNAs of all four patients with MEN2B and in 7 of the 33 sporadic MTCs. Germline mutations of codon 768, GAG to GAC (Glu to Asp), were detected in two patients with sporadic MTCs. We also identified two novel somatic mutations in sporadic MTCs, one at codon 631 (Asp to Gly) and the other at codon 634 (Cys to Arg). These two mutations will contrlbute to study functional domains of the RET protein.