Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer

Nature Genetics volume 30, pages 406–410 (2002)Cite this article

Abstract

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis1,2,3. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3–q43 (refs 4–6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency7,8,9,10,11, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor12,13,14.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Critical recombinants in family 304 and cosegregation of disease with the FH mutation.
Figure 2: Germline deletion in family 713.
Figure 3: Germline FH mutations.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Vikhlyaeva, E.M., Khodzhaeva, Z.S. & Fantschenko, N.D. Familial predisposition to uterine leiomyomas. Int. J. Gynaecol. Obstet. 51, 127–131 (1995).

    Article  CAS  Google Scholar 

  2. Luoto, R. et al. Heritability and risk factors of uterine fibroids—the Finnish Twin Cohort study. Maturitas 37, 15–26 (2000).

    Article  CAS  Google Scholar 

  3. Takamizawa, S. et al. Risk of complications and uterine malignancies in women undergoing hysterectomy for presumed benign leiomyomas. Gynecol. Obstet. Invest. 48, 193–196 (1999).

    Article  CAS  Google Scholar 

  4. Alam, N.A. et al. Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3–q43. Am. J. Hum. Genet. 68, 1264–1269 (2001).

    Article  CAS  Google Scholar 

  5. Kiuru, M. et al. Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am. J. Pathol. 159, 825–829 (2001).

    Article  CAS  Google Scholar 

  6. Launonen, V. et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc. Natl Acad. Sci. USA 98, 3387–3392 (2001).

    Article  CAS  Google Scholar 

  7. Gellera, C. et al. Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. Neurology 40, 495–499 (1990).

    Article  CAS  Google Scholar 

  8. Liochev, S.I. & Fridovich, I. Fumarase C, the stable fumarase of Escherichia coli, is controlled by the soxRS regulon. Proc. Natl Acad. Sci. USA 89, 5892–5896 (1992).

    Article  CAS  Google Scholar 

  9. Bourgeron, T. et al. Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J. Clin. Invest. 93, 2514–2518 (1994).

    Article  CAS  Google Scholar 

  10. Rustin, P. et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim. Biophys. Acta 1361, 185–197 (1997).

    Article  CAS  Google Scholar 

  11. Coughlin, E.M. et al. Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol. Genet. Metab. 63, 254–262 (1998).

    Article  CAS  Google Scholar 

  12. Baysal, B.E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848–851 (2000).

    Article  CAS  Google Scholar 

  13. Niemann, S. & Muller, U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat. Genet. 26, 268–270 (2000).

    Article  CAS  Google Scholar 

  14. Astuti, D. et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69, 49–54 (2001).

    Article  CAS  Google Scholar 

  15. Hatch, M.D. A simple spectrophotometric assay for fumarate hydratase in crude tissue extracts. Anal. Biochem. 85, 271–275 (1978).

    Article  CAS  Google Scholar 

  16. Weaver, T., Lees, M. & Banaszak, L. Mutations of fumarase that distinguish between the active site and a nearby dicarboxylic acid binding site. Protein Sci. 6, 834–842 (1997).

    Article  CAS  Google Scholar 

  17. Kaelin, W.G. Jr & Maher, E.R. The VHL tumour-suppressor gene paradigm. Trends Genet. 14, 423–426 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the families involved and their clinicians (H.M. Nelson, E. Healy, A.C. Pembroke, E. Calonje, S. Jablonska, J.R.S. Rendall, P.J. August, P.S. Friedman, R. Ratnavel, C.S. Munro, P.W. Bowers, R.J. Mann, A. MacDonald, F. Camacho-Martinez, N.P. Burrows, C. Fuller, K. Dalziel, G. Guillet, A.C. Pembroke, J.A.R. Anderson, M.G. Davies, S.E. Hadfield-Jones, S.P. MacDonald- Hull, S.M. Wilkinson, R.H. Felix, J. Leonard and M. Suri). We thank E. Pukkala and the Finnish Cancer Registry for help in characterizing the Finnish families; S. Marttinen, S. Lindh, S. Lindroos, R. Mattlar, K. Laukkanen and A. Leskinen for technical assistance; and S. Gregory and C. Gillson for providing advice and BAC clones for FISH. Group 1 received support from the Imperial Cancer Research Fund and is grateful for help from the ICRF Equipment Park and Cell Production. Group 2 was supported by the Cancer Research Campaign and the Wellcome Trust. Group 3 was supported by grants from the Helsinki University Central Hospital, Biocentrum Helsinki, the Sigrid Juselius Foundation, the Finnish Cancer Society, the Finnish Medical Duodecim, Kidney Foundation and the Academy of Finland (Finnish Center of Excellence Programme).

Author information

Author notes

  1. N. Afrina Alam, Andrew J. Rowan, Stephen Bevan, Maija Kiuru and Rainer Lehtonen: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44, Lincoln's Inn Fields, WC2A 3PX, London, UK

    Ian P.M. Tomlinson, N. Afrina Alam, Andrew J. Rowan, Ella Barclay, Emma E. M. Jaeger, Patricia Gorman, Hanan Lamlum & Rebecca R. Roylance

  2. Center for Cutaneous Research, St Bartholomew's and London School of Medicine and Dentistry, Queen Mary College, University of London, Whitechapel, London, UK

    David Kelsell & Irene Leigh

  3. Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, London, UK

    Shamima Rahman

  4. Neonatal Screening and Chemical Pathology, Sheffield Children's Hospital, Sheffield, S10 2TH, UK

    Simon Olpin

  5. Section of Cancer Genetics, Haddow Laboratories, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK

    Stephen Bevan, Karen Barker, Nicholas Hearle & Richard S. Houlston

  6. Department of Medical Genetics, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014

    Maija Kiuru, Rainer Lehtonen, Auli Karhu, Susa Vilkki, Päivi Laiho, Carita Eklund, Kristiina Aittomäki, Reijo Salovaara, Virpi Launonen & Lauri A. Aaltonen

  7. University of Helsinki, Finland

    Maija Kiuru, Maija Kiuru, Maija Kiuru, Rainer Lehtonen, Rainer Lehtonen, Rainer Lehtonen, Auli Karhu, Auli Karhu, Auli Karhu, Susa Vilkki, Susa Vilkki, Susa Vilkki, Päivi Laiho, Päivi Laiho, Päivi Laiho, Carita Eklund, Carita Eklund, Carita Eklund, Kristiina Aittomäki, Kristiina Aittomäki, Kristiina Aittomäki, Reijo Salovaara, Reijo Salovaara, Reijo Salovaara, Virpi Launonen, Virpi Launonen, Virpi Launonen, Lauri A. Aaltonen, Lauri A. Aaltonen & Lauri A. Aaltonen

  8. Department of Clinical Genetics, Oulu University Hospital, Kajaanintie 52, Oulu, FIN-90220, Finland

    Outi Vierimaa

  9. Departments of Clinical Genetics (Kiinamyllynkatu 4–8) and Medical Genetics (Kiinamyllynkatu 10), Turku University Hospital, Turku, FIN-20520, Finland

    Marja Hietala

  10. Finnish Red Cross Blood Transfusion Service, Kivihaantie 7, Helsinki, FIN-00310, Finland

    Pertti Sistonen

  11. Department of Pathology, Haartman Institute, PO Box 21 (Haartmaninkatu 3)

    Anders Paetau & Reijo Salovaara

  12. University of Helsinki, Helsinki, FIN-00014, Finland

    Anders Paetau, Anders Paetau, Anders Paetau, Reijo Salovaara, Reijo Salovaara & Reijo Salovaara

  13. Department of Pathology, Oulu University Hospital, Kajaanintie 52, Oulu, FIN-90220, Finland

    Riitta Herva

Consortia

The Multiple Leiomyoma Consortium

  • Group 1

    • Ian P.M. Tomlinson
    • , N. Afrina Alam
    • , Andrew J. Rowan
    • , Ella Barclay
    • , Emma E. M. Jaeger
    • , David Kelsell
    • , Irene Leigh
    • , Patricia Gorman
    • , Hanan Lamlum
    • , Shamima Rahman
    • , Rebecca R. Roylance
    •  & Simon Olpin

  • Group 2

    • Stephen Bevan
    • , Karen Barker
    • , Nicholas Hearle
    •  & Richard S. Houlston

  • Group 3

    • Maija Kiuru
    • , Rainer Lehtonen
    • , Auli Karhu
    • , Susa Vilkki
    • , Päivi Laiho
    • , Carita Eklund
    • , Outi Vierimaa
    • , Kristiina Aittomäki
    • , Marja Hietala
    • , Pertti Sistonen
    • , Anders Paetau
    • , Reijo Salovaara
    • , Riitta Herva
    • , Virpi Launonen
    •  & Lauri A. Aaltonen

Corresponding authors

Correspondence to Ian P.M. Tomlinson, Richard S. Houlston or Lauri A. Aaltonen.

Ethics declarations

Competing interests

The author declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

The Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30, 406–410 (2002). https://doi.org/10.1038/ng849

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng849

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing