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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer
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A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer

机译：在Birt-Hogg-Dube（BHD）基因中插入种系会产生遗传性肾癌的Nihon大鼠模型

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摘要

A rat model of hereditary renal carcinoma (RC) was found in a rat colony of the Sprague-Dawley strain in Japan and named the "Nihon" rat. In heterozygotes, RCs, predominantly the clear cell type, develop from early preneoplastic lesions, which began to appear as early as 3 weeks of age, to adenocarcinomas by the age of 6 months. The Nihon rat is an example of a Mendelian domi-nantly inherited predisposition for development of RCs like the Eker (Tsc2 gene mutant) rat. We have previously shown that the Nihon mutation was tightly linked to genes that are located on the distal part of rat chromosome 10. The order of the genes is the Eker (Tsc2 gene (human 16p13.3)-Il3 gene-Nihon gene-Llg/l1 locus-Myhse gene. We now describe a germ-line mutation in the Birt-Hogg-Dube gene (Bhd) (human 17p11.2) caused by the insertion of a single nucleotide in the Nihon rat, resulting in a frameshift and producing a stop codon 26 aa downstream. We found that the homozygous mutant condition was lethal at an early stage of fetal life in the rat. We detected a high frequency of loss of heterozy-gosity (LOH) in primary RCs (10/11) at the Bhd locus and found a point mutation (nonsense) in one LOH-negative case, fitting Knud-son's "two-hit" model. The Nihon rat may therefore provide insights into a tumor-suppressor gene that is related to renal carcinogenesis and an animal model of human BHD syndrome.
机译：在日本的Sprague-Dawley品系的大鼠群体中发现了一种遗传性肾癌（RC）的大鼠模型，并将其命名为“ Nihon”大鼠。在杂合子中，RCs主要是透明细胞类型，从早期的肿瘤前病变开始发展，这种病变早在3周龄就开始出现，到6个月大时才发展为腺癌。 Nihon大鼠是孟德尔式遗传性易患RCs（例如Eker（Tsc2基因突变体）大鼠）易感性的一个例子。先前我们已经表明，Nihon突变与位于大鼠10号染色体远端的基因紧密相连。这些基因的顺序为Eker（Tsc2基因（人类16p13.3）-Il3基因-Nihon基因-Llg / l1位点Myhse基因。我们现在描述Birt-Hogg-Dube基因（Bhd）（人类17p11.2）中的种系突变，该突变是由在日本大鼠中插入单个核苷酸引起的，导致移码和在下游产生一个26 aa的终止密码子，我们发现纯合突变体条件在大鼠胎儿生命的早期阶段具有致死性，我们在原代RC中检测到杂合性丢失（LOH）的频率很高（10/11）在Bhd的所在地，发现了一例LOH阴性的点突变（无意义），符合Knud-son的“两次打击”模型，因此，Nihon大鼠可能提供有关与肾癌发生和发展相关的肿瘤抑制基因的见解。人类BHD综合征的动物模型。

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