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.
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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).
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Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation
Cell Death & Disease (2018)