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

Multiple Leiomyoma Consortium, Ian P. M. Tomlinson, N. Afrina Alam, Andrew J. Rowan, Ella Barclay, Emma E. M. Jaeger, David Kelsell, Irene Leigh, Patricia Gorman, Hanan Lamlum, Shamima Rahman, Rebecca R. Roylance, Simon Olpin, Stephen Bevan, Karen Barker, Nicholas Hearle, Richard S. Houlston, Maija Kiuru, Rainer Lehtonen, Auli Karhu & 12 others Susa Vilkki, Paivi Laiho, Carita Eklund, Outi Vierimaa, Kristiina Aittomaki, Marja Hietala, Pertti Sistonen, Anders Paetau, Reijo Salovaara, Riitta Herva, Virpi Launonen, Lauri A. Aaltonen

    Research output: Contribution to journalArticle

    955 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)406-410
    Number of pages5
    JournalNature Genetics
    Volume30
    Issue number4
    DOIs
    Publication statusPublished - 2002

    Fingerprint

    Germ-Line Mutation
    Leiomyoma
    Renal Cell Carcinoma
    Fumarate Hydratase
    Leiomyomatosis
    Skin
    Mutation
    Housekeeping
    Neoplasms
    Citric Acid Cycle
    Mitochondrial Proteins
    Enzymes
    Genes
    Chromosomes
    Phenotype
    Amino Acids
    Proteins

    Keywords

    • Fumarate hydratase
    • Mitochondrial enzyme
    • Genomic DNA
    • Cancer susceptibility
    • Chromosome 14q
    • Citric acid cycle
    • Gene mapping
    • Gene mutation
    • Kidney carcinoma
    • Leiomyoma
    • Uterus myoma

    Cite this

    Multiple Leiomyoma Consortium, Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., ... Aaltonen, L. A. (2002). Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature Genetics, 30(4), 406-410. https://doi.org/10.1038/ng849
    Multiple Leiomyoma Consortium ; Tomlinson, Ian P. M. ; Alam, N. Afrina ; Rowan, Andrew J. ; Barclay, Ella ; Jaeger, Emma E. M. ; Kelsell, David ; Leigh, Irene ; Gorman, Patricia ; Lamlum, Hanan ; Rahman, Shamima ; Roylance, Rebecca R. ; Olpin, Simon ; Bevan, Stephen ; Barker, Karen ; Hearle, Nicholas ; Houlston, Richard S. ; Kiuru, Maija ; Lehtonen, Rainer ; Karhu, Auli ; Vilkki, Susa ; Laiho, Paivi ; Eklund, Carita ; Vierimaa, Outi ; Aittomaki, Kristiina ; Hietala, Marja ; Sistonen, Pertti ; Paetau, Anders ; Salovaara, Reijo ; Herva, Riitta ; Launonen, Virpi ; Aaltonen, Lauri A. / Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. In: Nature Genetics. 2002 ; Vol. 30, No. 4. pp. 406-410.
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    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 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.",
    keywords = "Fumarate hydratase, Mitochondrial enzyme, Genomic DNA, Cancer susceptibility, Chromosome 14q, Citric acid cycle, Gene mapping, Gene mutation, Kidney carcinoma, Leiomyoma, Uterus myoma",
    author = "{Multiple Leiomyoma Consortium} and Tomlinson, {Ian P. M.} and Alam, {N. Afrina} and Rowan, {Andrew J.} and Ella Barclay and Jaeger, {Emma E. M.} and David Kelsell and Irene Leigh and Patricia Gorman and Hanan Lamlum and Shamima Rahman and Roylance, {Rebecca R.} and Simon Olpin and Stephen Bevan and Karen Barker and Nicholas Hearle and Houlston, {Richard S.} and Maija Kiuru and Rainer Lehtonen and Auli Karhu and Susa Vilkki and Paivi Laiho and Carita Eklund and Outi Vierimaa and Kristiina Aittomaki and Marja Hietala and Pertti Sistonen and Anders Paetau and Reijo Salovaara and Riitta Herva and Virpi Launonen and Aaltonen, {Lauri A.}",
    note = "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)",
    year = "2002",
    doi = "10.1038/ng849",
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    pages = "406--410",
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    Multiple Leiomyoma Consortium, Tomlinson, IPM, Alam, NA, Rowan, AJ, Barclay, E, Jaeger, EEM, Kelsell, D, Leigh, I, Gorman, P, Lamlum, H, Rahman, S, Roylance, RR, Olpin, S, Bevan, S, Barker, K, Hearle, N, Houlston, RS, Kiuru, M, Lehtonen, R, Karhu, A, Vilkki, S, Laiho, P, Eklund, C, Vierimaa, O, Aittomaki, K, Hietala, M, Sistonen, P, Paetau, A, Salovaara, R, Herva, R, Launonen, V & Aaltonen, LA 2002, 'Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer', Nature Genetics, vol. 30, no. 4, pp. 406-410. https://doi.org/10.1038/ng849

    Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. / Multiple Leiomyoma Consortium; Tomlinson, Ian P. M.; Alam, N. Afrina; Rowan, Andrew J.; Barclay, Ella; Jaeger, Emma E. M.; Kelsell, David; Leigh, Irene; Gorman, Patricia; Lamlum, Hanan; Rahman, Shamima; Roylance, Rebecca R.; Olpin, Simon; Bevan, Stephen; Barker, Karen; Hearle, Nicholas; Houlston, Richard S.; Kiuru, Maija; Lehtonen, Rainer; Karhu, Auli; Vilkki, Susa; Laiho, Paivi; Eklund, Carita; Vierimaa, Outi; Aittomaki, Kristiina; Hietala, Marja; Sistonen, Pertti; Paetau, Anders; Salovaara, Reijo; Herva, Riitta; Launonen, Virpi; Aaltonen, Lauri A.

    In: Nature Genetics, Vol. 30, No. 4, 2002, p. 406-410.

    Research output: Contribution to journalArticle

    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

    VL - 30

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    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

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    ER -

    Multiple Leiomyoma Consortium, Tomlinson IPM, Alam NA, Rowan AJ, Barclay E, Jaeger EEM et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature Genetics. 2002;30(4):406-410. https://doi.org/10.1038/ng849