MUTATIONS IN THE RET PROTOONCOGENE ARE ASSOCIATED WITH MEN 2A AND FMTC
MUTATIONS IN THE RET PROTOONCOGENE ARE ASSOCIATED WITH MEN 2A AND FMTC
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DOI：
10.1093/hmg/2.7.851
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发表时间：
1993-07-01
影响因子：
3.5
通讯作者：
WELLS, SA
中科院分区：
文献类型：
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作者：
DONISKELLER, H;DOU, SS;WELLS, SA
多发性内分泌瘤2A型（MEN 2A）和家族性甲状腺髓样癌（FMTC）是显性遗传性疾病，易发生内分泌瘤。有证据表明，RET原癌基因，一个假定的跨膜酪氨酸激酶的编码区内的序列变化，可能是负责这些遗传性疾病的肿瘤的发展。在8个MEN 2A和4个FMTC家族中鉴定了RET原癌基因外显子7和8的单链构象变体（SSCV）。通过单倍型分析实验，仅在受影响或遗传了MEN2A或FMTC等位基因的个体的DNA中观察到变异。直接测序鉴定的七种变体。所有涉及点突变的密码子内指定的半胱氨酸残基，导致非保守性氨基酸的变化。七个突变中的六个位于外显子7。在外显子8中发现一个单一的突变。在4个MEN 2B家族中，所有可用的外显子检测均未检测到变异体，在16例有充分记录的散发性甲状腺髓样癌或嗜铬细胞瘤中，也未检测到外显子7变异体。突变与疾病的共同遗传以及RET原癌基因的物理和遗传接近性提供了证据，证明RET是MEN 2三种遗传形式中至少两种的原因。RET的正常功能和配体都还不清楚。然而，它明显参与这些遗传性肿瘤的发展，以及在甲状腺乳头状癌表明一个重要的发展或细胞调节作用的蛋白质。
Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.