Skip to main content

Advertisement

Log in

Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt–Hogg–Dubé syndrome

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

In the Nihon rat, an established model of hereditary renal cell carcinoma (RCC), the propensity for tumor development, is inherited as an autosomal dominant trait due to a single germline nucleotide insertion mutation in the rat Bhd ortholog. The Birt–Hogg–Dubé (BHD) syndrome is a rare autosomal dominant disease characterized by fibrofolliculoma, pulmonary cysts, spontaneous pneumothorax, and renal neoplasm. The renal lesions of the Nihon rat are characterized, and extrarenal lesions are also described in this work. The earliest lesion of the RCC was identified as an altered tubule at as early as 3 weeks of age and rapidly progressed through adenoma to carcinoma with the primary cell type being clear/acidophilic where some similarities were evident to RCCs in BHD syndrome. The Nihon rats demonstrate a heterotopic ossification within RCCs and three extrarenal lesions, clear cell hyperplasia/adenoma of the endometrium, clear cell change of the epithelium of striated portions of salivary glands, and cardiac rhabdomyomatosis. This rat model of hereditary RCC provides a useful tool for analyzing the series of events leading to renal tumorigenesis and for studying BHD gene functions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Aizawa S, Kikuchi Y, Suzuki M, Furusato M (1987) Renal cell carcinoma of lower nephron origin. Acta Pathol Jpn 37:567–574

    PubMed  CAS  Google Scholar 

  2. Akhtar M, Kardar H, Linjawi T, McClintock J, Ali MA (1995) Chromophobe cell carcinoma of the kidney. A clinicopathologic study of 21 cases. Am J Surg Pathol 19:1245–1256

    Article  PubMed  CAS  Google Scholar 

  3. Bannash P, Zerban H (1968) Renal cell adenoma and carcinoma, rat. In: Jones TC, Mohr U, Hunt RD (eds) Monographs on pathology of laboratory animals. Springer, Berlin Heidelberg New York, pp 112–139

    Google Scholar 

  4. Birt AR, Hogg GR, Dube WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113:1674–1677

    Article  PubMed  CAS  Google Scholar 

  5. Cochand-Priollet B, Molinie V, Bougaran J, Bouvier R, Dauge-Geffroy MC, Deslignieres S, Fournet JC, Gros P, Lesourd A, Saint-Andre JP, Toublanc M, Vieillefond A, Wassef M, Fontaine A, Groleau L (1997) Renal chromophobe cell carcinoma and oncocytoma. A comparative morphologic, histochemical, and immunohistochemical study of 124 cases. Arch Pathol Lab Med 121:1081–1086

    PubMed  CAS  Google Scholar 

  6. Cohen C, McCue PA, Derose PB (1988) Histogenesis of renal cell carcinoma and renal oncocytoma. An immunohistochemical study. Cancer 62:1946–1951

    Article  PubMed  CAS  Google Scholar 

  7. Eker R (1954) Familial renal adenomas in Wistar rats; a preliminary report. Acta Pathol Microbiol Scand 34:554–562

    Article  PubMed  CAS  Google Scholar 

  8. Eker R (1961) A dominant gene for renal adenomas in the rat. Nature 189:858–859

    Article  PubMed  Google Scholar 

  9. Everitt JI, Goldsworthy TL, Wolf DC, Walker CL (1992) Hereditary renal cell carcinoma in the Eker rat: a rodent familial cancer syndrome. J Urol 148:1932–1936

    PubMed  CAS  Google Scholar 

  10. Hino O, Klein-Szanto AJ, Freed JJ, Testa JR, Brown DQ, Vilensky M, Yeung RS, Tartof KD, Knudson AG (1993) Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. Proc Natl Acad Sci U S A 90:327–331

    Article  PubMed  CAS  Google Scholar 

  11. Hino O, Fukuda T, Satake N, Kobayashi T, Honda S, Orimoto K, Yamashita Y, Kikuchi Y (1999) TSC2 gene mutant (Eker) rat model of a Mendelian dominantly inherited cancer. Prog Exp Tumor Res 35:95–108

    PubMed  CAS  Google Scholar 

  12. Hino O, Okimoto K, Kouchi M, Sakurai J (2001) A novel renal carcinoma predisposing gene of the Nihon rat maps on chromosome 10. Jpn J Cancer Res 92:1147–1149

    PubMed  CAS  Google Scholar 

  13. The European Chromosome 16 Tuberous Sclerosis Consortium (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–1315

    Google Scholar 

  14. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ (2004) American Cancer Society. Cancer statistics, 2004. CA Cancer J Clin 54:8–29

    PubMed  Google Scholar 

  15. Kim MK, Kim S (2002) Immunohistochemical profile of common epithelial neoplasms arising in the kidney. Appl Immunohistochem Mol Morphol 10:332–338

    Article  PubMed  CAS  Google Scholar 

  16. Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O (1995) A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat Genet 9:70–74

    Article  PubMed  Google Scholar 

  17. Kouchi M, Okimoto K, Kikawa E, Toyosawa K, Koujitani T, Kuroki K, Tanaka K, Matsuoka N, Hino O (2001) “Nihon rat”, a novel rat model for renal cell carcinoma. Proc Jpn Animal Models Human Dis 17:16–19

    Google Scholar 

  18. Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, Eble JN, Fleming S, Ljungberg B, Medeiros LJ, Moch H, Reuter VE, Ritz E, Roos G, Schmidt D, Srigley JR, Storkel S, van den Berg E, Zbar B (1997) The Heidelberg classification of renal cell tumours. J Pathol 183:131–133

    Article  PubMed  CAS  Google Scholar 

  19. Krishnan B, Truong LD (2002) Renal epithelial neoplasms. The diagnostic implications of electron microscopic study in 55 cases. Hum Pathol 33:68–79

    Article  PubMed  Google Scholar 

  20. Langner C, Wegscheider BJ, Ratschek M, Schips L, Zigeuner R (2004) Keratin immunohistochemistry in renal cell carcinoma subtypes and renal oncocytomas: a systematic analysis of 233 tumors. Virchows Arch 444:127–134

    Article  PubMed  CAS  Google Scholar 

  21. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou FW, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng YK, Duan DSR, Dean M, Glavac D, Richards FM, Crossey PA, Ferguson-Smith MA, Lepaslier D, Chumakov I, Cohen D, Chinault AC, Maher ER, Linehan WM, Zbar B, lErman MI (1993) Identification of the von Hippel–Lindau disease tumor suppressor gene. Science 260:1317–1320

    Article  PubMed  CAS  Google Scholar 

  22. Lingaas F, Comstock KE, Kirkness EF, Sorensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA (2003) 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 12:3043–3053

    Article  PubMed  CAS  Google Scholar 

  23. Martignoni G, Pea M, Brunelli M, Chilosi M, Zamo A, Bertaso M, Cossu-Rocca P, Eble JN, Mikuz G, Puppa G, Badoual C, Ficarra V, Novella G, Bonetti F (2004) CD10 is expressed in a subset of chromophobe renal cell carcinomas. Mod Pathol 17:1455–1463

    Article  PubMed  CAS  Google Scholar 

  24. Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. N Engl J Med 335:865–875

    Article  PubMed  CAS  Google Scholar 

  25. Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS (2002) 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 2:157–164

    Article  PubMed  CAS  Google Scholar 

  26. Okimoto K, Kouchi M, Kikawa E, Toyosawa K, Koujitani T, Tanaka K, Matsuoka N, Sakurai J, Hino O (2000) A novel “Nihon” rat model of a Mendelian dominantly inherited renal cell carcinoma. Jpn J Cancer Res 91:1096–1099

    PubMed  CAS  Google Scholar 

  27. Okimoto K, Sakurai J, Kobayashi T, Mitani H, Hirayama Y, Nickerson ML, Warren MB, Zbar B, Schmidt LS, Hino O (2004) A germ-line insertion in the Birt–Hogg–Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer. Proc Natl Acad Sci U S A 101:2023–2027

    Article  PubMed  CAS  Google Scholar 

  28. Liu V, Kwan T, Page EH (2000) Parotid oncocytoma in the Birt–Hogg–Dube syndrome. J Am Acad Dermatol 43:1120–1122

    Article  PubMed  CAS  Google Scholar 

  29. Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ (2002) Renal tumors in the Birt–Hogg–Dubé syndrome. Am J Surg Pathol 26:1542–1552

    Article  PubMed  Google Scholar 

  30. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Zbar B (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16:68–73

    Article  PubMed  CAS  Google Scholar 

  31. Schoen RJ, Cotran RS (1999) Blood vessels. In: Cotran RS, Kumar V, Collins T (eds) Robbins pathologic basis of disease. Saunders, Philadelphia, pp 493–542

    Google Scholar 

  32. Sostre G, Johnson JF III, Cho M (1998) Ossifying renal cell carcinoma. Pediatr Radiol 28:458–460

    Article  PubMed  CAS  Google Scholar 

  33. Storkel S, Pannen B, Thoenes W, Steart PV, Wagner S, Drenckhahn D (1988) Intercalated cells as a probable source for the development of renal oncocytoma. Virchows Arch B Cell Pathol Incl Mol Pathol 56:185–189

    PubMed  CAS  Google Scholar 

  34. Storkel S, Steart PV, Drenckhahn D, Thoenes W (1989) The human chromophobe cell renal carcinoma: its probable relation to intercalated cells of the collecting duct. Virchows Arch B Cell Pathol Incl Mol Pathol 56:237–245

    Article  PubMed  CAS  Google Scholar 

  35. Storkel S, Eble JN, Adlakha K, Amin M, Blute ML, Bostwick DG, Darson M, Delahunt B, Iczkowski K (1997) Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80:987–989

    Article  PubMed  CAS  Google Scholar 

  36. Thoenes W, Storkel S, Rumpelt HJ (1985) Human chromophobe cell renal carcinoma. Virchows Arch B Cell Pathol Incl Mol Pathol 48:207–217

    PubMed  CAS  Google Scholar 

  37. Thoenes W, Storkel S, Rumpelt HJ, Moll R, Baum HP, Werner S (1988) Chromophobe cell renal carcinoma and its variants—a report on 32 cases. J Pathol 155:277–287

    Article  PubMed  CAS  Google Scholar 

  38. Tickoo SK, Amin MB, Zarbo RJ (1998) Colloidal iron staining in renal epithelial neoplasms, including chromophobe renal cell carcinoma: emphasis on technique and patterns of staining. Am J Surg Pathol 22:419–424

    Article  PubMed  CAS  Google Scholar 

  39. Tickoo SK, Lee MW, Eble JN, Amin M, Christopherson T, Zarbo RJ, Amin MB (2000) Ultrastructural observations on mitochondria and microvesicles in renal oncocytoma, chromophobe renal cell carcinoma, and eosinophilic variant of conventional (clear cell) renal cell carcinoma. Am J Surg Pathol 24:1247–1256

    Article  PubMed  CAS  Google Scholar 

  40. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30:406–410

    Article  PubMed  CAS  Google Scholar 

  41. Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, Linehan M, Turner ML (1999) Birt–Hogg–Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135:1195–1202

    Article  PubMed  CAS  Google Scholar 

  42. van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Shampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Stepp T, Ali JBM, Ward S, Green AJ, Yates JRW, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808

    Article  PubMed  Google Scholar 

  43. Weirich G, Glenn G, Junker K, Merino M, Storkel S, Lubensky I, Choyke P, Pack S, Amin M, Walther MM, Linehan WM, Zbar B (1998) Familial renal oncocytoma: clinicopathological study of 5 families. J Urol 160:335–340

    Article  PubMed  CAS  Google Scholar 

  44. Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM (2002) Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt–Hogg–Dubé syndrome. Cancer Epidemiol Biomarkers Prev 11:393–400

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs. Toshiyuki Kobayashi and Kazuyasu Kijima for their help. This work was supported by a Grant-in-Aid for Cancer Research and Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, and Science and Technology of Japan and the Ministry of Health, Labour, and Welfare of Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mami Kouchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kouchi, M., Okimoto, K., Matsumoto, I. et al. Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt–Hogg–Dubé syndrome. Virchows Arch 448, 463–471 (2006). https://doi.org/10.1007/s00428-005-0142-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-005-0142-9

Keywords

Navigation