| Note | |
| Entity | Uterine Leiomyomata (UL) |
| Note | Synonyms include uterine fibroids, fibromas, myofibromas and myomas. |
| Disease | Benign mesenchymal tumors of the uterus. |
| Prognosis | Excellent, but may require surgical intervention as one- third of hysterectomies performed in the United States have a primary indication of UL. |
| Cytogenetics | UL rarely associated with cytologically visible 1q42 deletions. |
| Hybrid/Mutated Gene | Deletions of FH from structural rearrangements of 1q42.1. |
| Abnormal Protein | Presumed haploinsufficiency or functional null if mutation in other FH allele occurs. |
| | |
| Entity | Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)/ multiple cutaneous and uterine leiomyomatosis (MCUL1). |
| Note | Also known as Reed's syndrome. |
| Disease | HLRCC is an autosomal dominant disorder, characterized by smooth muscle tumors of the skin and uterus and/or kidney. |
| Prognosis | Good, if early diagnosis. |
| Abnormal Protein | Inherited mutations can predispose to somatic deletions resulting in truncated, non-functional or absent proteins. |
| Oncogenesis | FH acts as classic tumor suppressor gene in HLRCC/MCUL1. Genetic or epigenetic alterations in FH resulting from substitution, deletion or methylation follow the Knudson 'two hit' mechanism. The resulting functionally null state for fumarase can lead to subsequent oxidative tissue damage and tumorigenesis. |
| | |
| Entity | Fumarate hydratase deficiency (FHD). |
| Note | Synonymous with fumarase deficiency and fumaric aciduria. |
| Disease | Autosomal recessive condition characterized by delayed development, diminished muscle tone, and encephalopathy likely due to limited energy generation during development. |
| Prognosis | Poor. FHD is a rare condition, but reported cases indicate most affected individuals survive only several months while very few survive into their third decade. |
| Hybrid/Mutated Gene | The most common allelic abnormality is a 3 base pair- AAA insertion. |
| Abnormal Protein | Mutations near fumarase active site result in absent or truncated protein. |
| | |
| Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. |
| Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, Potts ED, Crone M, Wilkinson S, Camacho-Martinez F, Jablonska S, Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S, Tomlinson IP |
| Human molecular genetics. 2003 ; 12 (11) : 1241-1252. |
| PMID 12761039 |
| |
| Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas. |
| Barker KT, Bevan S, Wang R, Lu YJ, Flanagan AM, Bridge JA, Fisher C, Finlayson CJ, Shipley J, Houlston RS |
| British journal of cancer. 2002 ; 87 (4) : 446-448. |
| PMID 12177782 |
| |
| Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies. |
| Gross KL, Panhuysen CI, Kleinman MS, Goldhammer H, Jones ES, Nassery N, Stewart EA, Morton CC |
| Genes, chromosomes & cancer. 2004 ; 41 (3) : 183-190. |
| PMID 15334541 |
| |
| Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. |
| Kiuru M, Launonen V, Hietala M, Aittomäki K, Vierimaa O, Salovaara R, Arola J, Pukkala E, Sistonen P, Herva R, Aaltonen LA |
| The American journal of pathology. 2001 ; 159 (3) : 825-829. |
| PMID 11549574 |
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| Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. |
| Kiuru M, Lehtonen R, Arola J, Salovaara R, Järvinen H, Aittomäki K, Sjöberg J, Visakorpi T, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, Karhu A, Aaltonen LA |
| Cancer research. 2002 ; 62 (16) : 4554-4557. |
| PMID 12183404 |
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| Inherited susceptibility to uterine leiomyomas and renal cell cancer. |
| Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA |
| Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (6) : 3387-3392. |
| PMID 11248088 |
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| The genetics of uterine leiomyomata: what clinicians need to know. |
| Stewart EA, Morton CC |
| Obstetrics and gynecology. 2006 ; 107 (4) : 917-921. |
| PMID 16582132 |
| |
| Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. |
| Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, 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, Aittomäki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Multiple Leiomyoma Consortium, Aaltonen LA |
| Nature genetics. 2002 ; 30 (4) : 406-410. |
| PMID 11865300 |
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| Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. |
| Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B |
| American journal of human genetics. 2003 ; 73 (1) : 95-106. |
| PMID 12772087 |
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| Distinct expression profile in fumarate-hydratase-deficient uterine fibroids. |
| Vanharanta S, Pollard PJ, Lehtonen HJ, Laiho P, Sjöberg J, Leminen A, Aittomäki K, Arola J, Kruhoffer M, Orntoft TF, Tomlinson IP, Kiuru M, Arango D, Aaltonen LA |
| Human molecular genetics. 2006 ; 15 (1) : 97-103. |
| PMID 16319128 |
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| Crystallographic studies of the catalytic and a second site in fumarase C from Escherichia coli. |
| Weaver T, Banaszak L |
| Biochemistry. 1996 ; 35 (44) : 13955-13965. |
| PMID 8909293 |
| |
| Mitochondrial and cytoplasmic fumarases in Saccharomyces cerevisiae are encoded by a single nuclear gene FUM1. |
| Wu M, Tzagoloff A |
| The Journal of biological chemistry. 1987 ; 262 (25) : 12275-12282. |
| PMID 3040736 |
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