Nature Genetics30, 406 - 410 (2002)
Published online: 25 February 2002; | doi:10.1038/ng849
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer
The Multiple Leiomyoma Consortium: Group 1: Ian P.M. Tomlinson1, N. Afrina Alam1, 12, Andrew J. Rowan1, 12, Ella Barclay1, Emma E. M. Jaeger1, David Kelsell2, Irene Leigh2, Patricia Gorman1, Hanan Lamlum1, Shamima Rahman3, Rebecca R. Roylance1
& Simon Olpin4Group 2: Stephen Bevan5, 12, Karen Barker5, Nicholas Hearle5
& Richard S. Houlston5Group 3: Maija Kiuru6, 12, Rainer Lehtonen6, 12, Auli Karhu6, Susa Vilkki6, Päivi Laiho6, Carita Eklund6, Outi Vierimaa7, Kristiina Aittomäki6, Marja Hietala8, Pertti Sistonen9, Anders Paetau10, Reijo Salovaara6, 10, Riitta Herva11, Virpi Launonen6
& Lauri A. Aaltonen6
1
Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44, Lincoln's Inn Fields, London WC2A 3PX, UK.
2
Center for Cutaneous Research, St Bartholomew's and London School of Medicine and Dentistry, Queen Mary College, University of London, Whitechapel, London, UK.
3
Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, London, UK.
4
Neonatal Screening and Chemical Pathology, Sheffield Children's Hospital, Sheffield S10 2TH, UK.
6
Department of Medical Genetics, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Finland.
7
Department of Clinical Genetics, Oulu University Hospital, Kajaanintie 52, FIN-90220 Oulu, Finland.
8
Departments of Clinical Genetics (Kiinamyllynkatu 4−8) and Medical Genetics (Kiinamyllynkatu 10), Turku University Hospital, FIN-20520 Turku, Finland.
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.
