MUTATIONS OF THE RET PROTOONCOGENE IN HIRSCHSPRUNGS-DISEASE
MUTATIONS OF THE RET PROTOONCOGENE IN HIRSCHSPRUNGS-DISEASE
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DOI：
10.1038/367378a0
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发表时间：
1994-01-27
期刊：
影响因子：
64.8
通讯作者：
MUNNICH, A
中科院分区：
文献类型：
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作者：
EDERY, P;LYONNET, S;MUNNICH, A
HIRSCHSPRUNG病（HSCR）是一种常见病（每5000个活产儿中就有1例），可导致新生儿肠梗阻和婴幼儿及成人巨结肠。这种疾病被认为是由于在后肠末端缺乏来自神经嵴的自主神经节细胞。分离分析表明家族性HSCR5不完全渗透显性遗传。最近，HSCR的一个基因被定位到染色体10q11.2上（参考文献6,7）。RET原癌基因8（一种在神经嵴细胞中表达的蛋白酪氨酸激酶基因）的位点与疾病位点之间未观察到重组。在这里，我们报告了6个不相关先证者中RET蛋白胞外结构域（外显子，2,3,5和6）的无义和错义突变，并表明突变基因型在HSCR家族中与疾病分离。RET突变在多发性内分泌肿瘤2A型（MEN 2A）中已有报道11,12。因此，RET基因的种系突变可能导致HSCR的发育异常，也可能导致MEN 2A的遗传易感性。
HIRSCHSPRUNG'S disease (HSCR)1 is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates2 and megacolon in infants and adults3. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut4. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR5. Recently, a gene for HSCR has been mapped to chromosome 10q11.2 (refs 6, 7). No recombination was observed between the disease locus and the locus for the RET proto-oncogene8, a protein tyrosine kinase gene expressed in the cells derived from the neural crest9,10. Here we report nonsense and missense mutations in the extracellular domain of RET protein (exons, 2, 3, 5, and 6) in six unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A)11,12. Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.