title: Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
abstract: Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. 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 deficiency, 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 tumor.
authors.affiliation: Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44, Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: N Afrina
authors.initials: NA
authors.lastname: Alam
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rowan
authors.forename: Ella
authors.initials: E
authors.lastname: Barclay
authors.forename: Emma E M
authors.initials: EE
authors.lastname: Jaeger
authors.forename: David
authors.initials: D
authors.lastname: Kelsell
authors.forename: Irene
authors.initials: I
authors.lastname: Leigh
authors.forename: Patricia
authors.initials: P
authors.lastname: Gorman
authors.forename: Hanan
authors.initials: H
authors.lastname: Lamlum
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Roylance
authors.forename: Simon
authors.initials: S
authors.lastname: Olpin
authors.forename: Stephen
authors.initials: S
authors.lastname: Bevan
authors.forename: Karen
authors.initials: K
authors.lastname: Barker
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hearle
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Maija
authors.initials: M
authors.lastname: Kiuru
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehtonen
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Susa
authors.initials: S
authors.lastname: Vilkki
authors.forename: Päivi
authors.initials: P
authors.lastname: Laiho
authors.forename: Carita
authors.initials: C
authors.lastname: Eklund
authors.forename: Outi
authors.initials: O
authors.lastname: Vierimaa
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Marja
authors.initials: M
authors.lastname: Hietala
authors.forename: Pertti
authors.initials: P
authors.lastname: Sistonen
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Reijo
authors.initials: R
authors.lastname: Salovaara
authors.forename: Riitta
authors.initials: R
authors.lastname: Herva
authors.forename: Virpi
authors.initials: V
authors.lastname: Launonen
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000483:Alleles; D002291:Carcinoma, Papillary / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1; D005091:Exons; D005260:Female; D005649:Fumarate Hydratase / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005799:Genes, Dominant; D005819:Genetic Markers; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics*; D007889:Leiomyoma / Q000235:genetics*; D018230:Leiomyoma, Epithelioid / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D005649:Fumarate Hydratase