A Germ-line Insertion in the Birt-Hogg-Dubé (BHD) Gene Gives Rise to the Nihon Rat Model of Inherited Renal Cancer

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Feb 11

PMID 14769940

Citations 27

Authors

Kazuo Okimoto

Junko Sakurai

Toshiyuki Kobayashi

Hiroaki Mitani

Youko Hirayama

Michael L Nickerson

Michelle B Warren

Berton Zbar

Laura S Schmidt

Okio Hino

Affiliations

Soon will be listed here.

Abstract

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 dominantly 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-Llgl1 locus- Myhse gene. We now describe a germ-line mutation in the Birt-Hogg-Dubé 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 heterozygosity (LOH) in primary RCs (10/11) at the Bhd locus and found a point mutation (nonsense) in one LOH-negative case, fitting Knudson'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.

Citing Articles

Positional cloning of rat mutant genes reveals new functions of these genes.

Kuramoto T Exp Anim. 2022; 72(1):1-8.

PMID: 36058846 PMC: 9978133. DOI: 10.1538/expanim.22-0089.

Folliculin variants linked to Birt-Hogg-Dubé syndrome are targeted for proteasomal degradation.

Clausen L, Stein A, Gronbaek-Thygesen M, Nygaard L, Soltoft C, Nielsen S PLoS Genet. 2020; 16(11):e1009187.

PMID: 33137092 PMC: 7660926. DOI: 10.1371/journal.pgen.1009187.

Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes.

Szpirer C J Biomed Sci. 2020; 27(1):84.

PMID: 32741357 PMC: 7395987. DOI: 10.1186/s12929-020-00673-8.

Choosing The Right Animal Model for Renal Cancer Research.

Sobczuk P, Brodziak A, Khan M, Chhabra S, Fiedorowicz M, Welniak-Kaminska M Transl Oncol. 2020; 13(3):100745.

PMID: 32092671 PMC: 7036425. DOI: 10.1016/j.tranon.2020.100745.

Renal transplantation in Birt-Hogg-Dubé syndrome: should we?.

Coutinho J, De Sa J, Teixeira F, Reis Santos C, Chorao R, Filipe R BMC Nephrol. 2018; 19(1):267.

PMID: 30326848 PMC: 6192299. DOI: 10.1186/s12882-018-1064-5.

References

Nickerson M, Warren M, Toro J, Matrosova V, Glenn G, Turner M . Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell. 2002; 2(2):157-64. DOI: 10.1016/s1535-6108(02)00104-6. View

Fukuda T, Tani Y, Kobayashi T, Hirayama Y, Hino O . A new Western blotting method using polymer immunocomplexes: detection of Tsc1 and Tsc2 expression in various cultured cell lines. Anal Biochem. 2000; 285(2):274-6. DOI: 10.1006/abio.2000.4787. View

Khoo S, Bradley M, Wong F, Hedblad M, Nordenskjold M, Teh B . Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene. 2001; 20(37):5239-42. DOI: 10.1038/sj.onc.1204703. View

Streisinger G, Okada Y, Emrich J, Newton J, Tsugita A, Terzaghi E . Frameshift mutations and the genetic code. This paper is dedicated to Professor Theodosius Dobzhansky on the occasion of his 66th birthday. Cold Spring Harb Symp Quant Biol. 1966; 31:77-84. DOI: 10.1101/sqb.1966.031.01.014. View

Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O . A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat Genet. 1995; 9(1):70-4. DOI: 10.1038/ng0195-70. View

Hino O, Klein-Szanto A, FREED J, Testa J, Brown D, Vilensky M . Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. Proc Natl Acad Sci U S A. 1993; 90(1):327-31. PMC: 45653. DOI: 10.1073/pnas.90.1.327. View

Satake N, Kobayashi T, Kobayashi E, Izumi K, Hino O . Isolation and characterization of a rat homologue of the human tuberous sclerosis 1 gene (Tsc1) and analysis of its mutations in rat renal carcinomas. Cancer Res. 1999; 59(4):849-55. View

Okimoto K, Kouchi M, Kikawa E, Toyosawa K, Koujitani T, Tanaka K . A novel "Nihon" rat model of a Mendelian dominantly inherited renal cell carcinoma. Jpn J Cancer Res. 2000; 91(11):1096-9. PMC: 5926279. DOI: 10.1111/j.1349-7006.2000.tb00890.x. View

Hino O, Okimoto K, Kouchi M, Sakurai J . A novel renal carcinoma predisposing gene of the Nihon rat maps on chromosome 10. Jpn J Cancer Res. 2001; 92(11):1147-9. PMC: 5926659. DOI: 10.1111/j.1349-7006.2001.tb02133.x. View

10.

Schmidt L, Warren M, Nickerson M, Weirich G, Matrosova V, Toro J . Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet. 2001; 69(4):876-82. PMC: 1226073. DOI: 10.1086/323744. View

11.

Birt A, HOGG G, Dube W . Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977; 113(12):1674-7. View

12.

Yeung R, Xiao G, Jin F, Lee W, Testa J, Knudson A . Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci U S A. 1994; 91(24):11413-6. PMC: 45241. DOI: 10.1073/pnas.91.24.11413. View

13.

Lingaas F, Comstock K, Kirkness E, Sorensen A, Aarskaug T, Hitte C . A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Hum Mol Genet. 2003; 12(23):3043-53. DOI: 10.1093/hmg/ddg336. View