Letter | Published:

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

Nature Genetics volume 30, pages 406410 (2002) | Download Citation



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,​5,​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.

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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

    • N. Afrina Alam
    • , Andrew J. Rowan
    • , Stephen Bevan
    • , Maija Kiuru
    •  & Rainer Lehtonen

    These authors contributed equally to this work.


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

    • Maija Kiuru
    • , Rainer Lehtonen
    • , Auli Karhu
    • , Susa Vilkki
    • , Päivi Laiho
    • , Carita Eklund
    • , Kristiina Aittomäki
    • , Reijo Salovaara
    • , Virpi Launonen
    •  & Lauri A. Aaltonen
  7. Department of Clinical Genetics, Oulu University Hospital, Kajaanintie 52, FIN-90220 Oulu, Finland.

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

    • Marja Hietala
  9. Finnish Red Cross Blood Transfusion Service, Kivihaantie 7, FIN-00310 Helsinki, Finland.

    • Pertti Sistonen
  10. Department of Pathology, Haartman Institute, PO Box 21 (Haartmaninkatu 3), University of Helsinki, FIN-00014 Helsinki, Finland.

    • Anders Paetau
    •  & Reijo Salovaara
  11. Department of Pathology, Oulu University Hospital, Kajaanintie 52, FIN-90220 Oulu, Finland.

    • Riitta Herva


  1. The Multiple Leiomyoma Consortium

    Group 1

    Group 2

    Group 3


    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

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

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