{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:05:14Z","timestamp":1792692314634,"version":"4.5.0"},"reference-count":15,"publisher":"National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,2,17]]},"abstract":"<jats:p>\n                    A rat model of hereditary renal carcinoma (RC) was found in a rat colony of the Sprague\u2013Dawley strain in Japan and named the \u201cNihon\u201d 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 dominantly inherited predisposition for development of RCs like the Eker (\n                    <jats:italic>Tsc2<\/jats:italic>\n                    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 (\n                    <jats:italic>Tsc2<\/jats:italic>\n                    gene (human 16p13.3)\u2013\n                    <jats:italic>Il3<\/jats:italic>\n                    gene\u2013Nihon gene\u2013\n                    <jats:italic>Llgl1<\/jats:italic>\n                    locus\u2013\n                    <jats:italic>Myhse<\/jats:italic>\n                    gene. We now describe a germ-line mutation in the Birt\u2013Hogg\u2013Dub\u00e9 gene (\n                    <jats:italic>Bhd<\/jats:italic>\n                    ) (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 heterozygosity (LOH) in primary RCs (10\/11) at the\n                    <jats:italic>Bhd<\/jats:italic>\n                    locus and found a point mutation (nonsense) in one LOH-negative case, fitting Knudson's \u201ctwo-hit\u201d 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0308071100","type":"journal-article","created":{"date-parts":[[2004,2,17]],"date-time":"2004-02-17T15:32:02Z","timestamp":1077031922000},"page":"2023-2027","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":79,"title":["A germ-line insertion in the Birt\u2013Hogg\u2013Dub\u00e9 (\n                    <i>BHD<\/i>\n                    ) gene gives rise to the Nihon rat model of inherited renal cancer"],"prefix":"10.1073","volume":"101","author":[{"given":"Kazuo","family":"Okimoto","sequence":"first","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Mitani","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youko","family":"Hirayama","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Nickerson","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle B.","family":"Warren","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berton","family":"Zbar","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura S.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Okio","family":"Hino","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Toxicology and Teratology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan; and Laboratory of Immunobiology, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation (SAIC)-Frederick, Inc., National Cancer Institute,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,2,9]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/189858b0"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0195-70"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.24.11413"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2000.tb00890.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1538\/expanim1992.17.16"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2001.tb02133.x"},{"key":"e_1_3_2_7_2","first-page":"876","volume":"69","year":"2002","unstructured":"Schmidt, L. 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