TY - JOUR
T1 - Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer
AU - Multiple Leiomyoma Consortium
AU - Tomlinson, Ian P. M.
AU - Alam, N. Afrina
AU - Rowan, Andrew J.
AU - Barclay, Ella
AU - Jaeger, Emma E. M.
AU - Kelsell, David
AU - Leigh, Irene
AU - Gorman, Patricia
AU - Lamlum, Hanan
AU - Rahman, Shamima
AU - Roylance, Rebecca R.
AU - Olpin, Simon
AU - Bevan, Stephen
AU - Barker, Karen
AU - Hearle, Nicholas
AU - Houlston, Richard S.
AU - Kiuru, Maija
AU - Lehtonen, Rainer
AU - Karhu, Auli
AU - Vilkki, Susa
AU - Laiho, Paivi
AU - Eklund, Carita
AU - Vierimaa, Outi
AU - Aittomaki, Kristiina
AU - Hietala, Marja
AU - Sistonen, Pertti
AU - Paetau, Anders
AU - Salovaara, Reijo
AU - Herva, Riitta
AU - Launonen, Virpi
AU - Aaltonen, Lauri A.
N1 - dc.publisher: Nature Publishing Group
dc.description.sponsorship: Imperial Cancer Research Fund
Cancer Research Campaign
Wellcome Trust
Helsinki University Central Hospital
Biocentrum Helsinki
Sigrid Juselius Foundation
Finnish Cancer Society
Finnish Medical Duodecim
Kidney Foundation
Academy of Finland (Finnish Center of Excellence Programme)
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Fumarate hydratase
KW - Mitochondrial enzyme
KW - Genomic DNA
KW - Cancer susceptibility
KW - Chromosome 14q
KW - Citric acid cycle
KW - Gene mapping
KW - Gene mutation
KW - Kidney carcinoma
KW - Leiomyoma
KW - Uterus myoma
U2 - 10.1038/ng849
DO - 10.1038/ng849
M3 - Article
C2 - 11865300
SN - 1061-4036
VL - 30
SP - 406
EP - 410
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -