Germline Fumarate Hydratase Mutations in Families with Multiple Cutaneous and Uterine Leiomyomata

Martı́nez-Mir, Amalia; Gläser, Benjamin; Chuang, Gary S.; Horev, Liran; Waldman, Arie; Engler, Danielle E.; Gordon, Derek; Spelman, Lynda; Hatzibougias, I; Green, Jack; Christiano, Angela M.; Zlotogorski, Abraham

doi:10.1046/j.1523-1747.2003.12499.x

Cited by 61 publications

(57 citation statements)

References 11 publications

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“…There have been 27 distinct missense mutations of 26 different residues reported (one residue has two reported mutations R190H and R190L as mentioned above). 1,[5][6][7]17 Missense mutations in MCUL appear to cluster in certain regions in the protein (Figure 2). These include the regions: P131 to M152 (P131R, H137R and Q142R, S144L, N145S, M152T, H153R the first two mapping to the B-site and the remaining five to the A-site); I186 to R190 (delI186, I186T, K187R, R190H, and R190L, all at the A-site); A265 to N297(A265T, N267Y, F269C, H275Y, V279D, L292P, and N297D all involved in subunit-subunit interaction); and E312 to S323 (E312K, N318K, E319Q, S322G, and S323N, all at the A-site).…”

Section: Resultsmentioning

confidence: 99%

“…These included 10 US families reported by Toro and colleagues 6 and two families from our UK study group who were of Spanish origin and had a shared ancestral hap- The H275Y mutation had also been reported in one MCUL/HLRCC family without renal cancer. 7 Missense mutations reported in FHD are summarized in Tables 4 and 5. They appear to cluster in some of the same regions as MCUL mutations (Figures 2 and 3).…”

Section: Resultsmentioning

confidence: 99%

“…These 27 distinct missense mutations represent 55 of 81 (68%) of the FH mutations reported in MCUL probands. 1,[5][6][7] The FH locus encodes two isoforms of fumarate hydratase, cytosolic and mitochondrial, which differ only in that the latter has an initial mitochondrial signal peptide. Fumarate hydratase catalyzes the stereospecific reversible hydration of fumarate to L-malate.…”

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Missense Mutations in Fumarate Hydratase in Multiple Cutaneous and Uterine Leiomyomatosis and Renal Cell Cancer

Alam

Olpin

Rowan

et al. 2005

The Journal of Molecular Diagnostics

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Heterozygous germline mutations in fumarate hydratase (FH) predispose to the multiple cutaneous and uterine leiomyomatosis syndrome (MCUL), which, when co-existing with renal cancer, is also known as hereditary leiomyomatosis and renal cell cancer. Twenty-seven distinct missense mutations represent 68% of FH mutations reported in MCUL. Here we show that FH missense mutations significantly occurred in fully conserved residues and in residues functioning in the FH A-site, B-site, or subunit-interacting region. Of 24 distinct missense mutations, 13 (54%) occurred in the substrate-binding Asite, 4 (17%) in the substrate-binding B-site, and 7 (29%) in the subunit-interacting region. Clustering of missense mutations suggested the presence of possible mutational hotspots. FH functional assay of lymphoblastoid cell lines from 23 individuals with heterozygous FH missense mutations showed that A-site mutants had significantly less residual activity than B-site mutants, supporting data from Escherichia coli that the A-site is the main catalytic site. Missense FH mutations predisposing to renal cancer had no unusual features, and identical mutations were found in families without renal cancer, suggesting a role for genetic or environmental factors in renal cancer development In the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomatosis (MCUL, Reed syndrome, leiomyomatosis cutis et uteri, multiple leiomyomatosis; OMIM 150800), affected females develop uterine leiomyomas and affected individuals of both sexes develop cutaneous leiomyomas. 1 Cutaneous leiomyomas are believed to be derived from the smooth muscle of the pilo-arrector apparatus. They generally present in the second, third, or fourth decades, typically as grouped papules or nodules on the trunk or limbs and are characteristically painful particularly in response to low temperatures or touch. Uterine leiomyomas or fibroids in MCUL are severely symptomatic with a large proportion of patients requiring symptom control by hysterectomy. 2 A small proportion of families with MCUL also cluster renal cancer, either papillary renal type II cancer or renal collecting duct cancer. 1,[3][4][5][6] This disease variant has been referred to as hereditary leiomyomatosis and renal cancer (HLRCC, OMIM 605839). MCUL/HLRCC has been found to be caused by germline mutations in fumarate hydratase (FH) in the majority of screened cases. 1,5,6 Forty-six distinct FH mutations have been reported to date in MCUL/HLRCC. Twenty-seven of these are missense mutations of 26 different residues (one residue has two reported mutations, R190H and R190L). These 27 distinct missense mutations represent 55 of 81 (68%) of the FH mutations reported in MCUL probands. 1,[5][6][7] The FH locus encodes two isoforms of fumarate hydratase, cytosolic and mitochondrial, which differ only in that the latter has an initial mitochondrial signal peptide. Fumarate hydratase catalyzes the stereospecific reversible hydration of fumarate to L-malate. The mitochondrial isoform performs this reactio...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Missense Mutations in Fumarate Hydratase in Multiple Cutaneous and Uterine Leiomyomatosis and Renal Cell Cancer

Alam

Olpin

Rowan

et al. 2005

The Journal of Molecular Diagnostics

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“…Individuals with cutaneous leiomyoma and renal cell tumors of one of three types (papillary type 2 (refs. 74-78)), collecting duct, 71,74,75 and tubulopapillary 78 ) should receive genetic counseling referral. 79,80 Although studies of the proportion of isolated cases of cutaneous leiomyomas with an FH mutation are not available, 85% of individuals with cutaneous leiomyomas (some of whom were isolated cases and some of whom had a family history of uterine leiomyoma or renal cell tumors) had an FH mutation in several studies.…”

Section: Hereditary Leiomyomatosis and Renal Cell Cancer (Omim 605839mentioning

confidence: 99%

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

Hampel

Bennett

Buchanan

et al. 2015

Genetics in Medicine

467

326

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Cancer genetic consultation services include the evaluation of patients' personal and family history for concerning features of hereditary cancer predisposition syndromes, development of a differential diagnosis for one or more possible hereditary cancer syndromes, genetic testing if indicated and available, recommendations for management, cancer surveillance and prevention, and information regarding genetic counseling and genetic testing for at-risk relatives. This counseling is informed by the genetic Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peerreviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their firstdegree relatives meet any of these referral criteria.

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“…8 In a large Tunisian Jewish pedigree, the mutation was associated with reduced penetrance for skin and uterine lesions in carrier females, but RCC was noted. 9,10 In a Dutch family, the mutation was associated with cutaneous and uterine leiomyomas but not RCC. 1 Now, with a fourth reported family with the same mutation (this report), it is apparent that penetrance of all key features, including RCC, may depend on other genetic or environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Melanoma and basal cell carcinoma in the hereditary leiomyomatosis and renal cell cancer syndrome. An expansion of the oncologic spectrum.

Sommer

Schnur

Heymann

2017

J Dermatol Case Rep

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Germline Fumarate Hydratase Mutations in Families with Multiple Cutaneous and Uterine Leiomyomata

Cited by 61 publications

References 11 publications

Missense Mutations in Fumarate Hydratase in Multiple Cutaneous and Uterine Leiomyomatosis and Renal Cell Cancer

Missense Mutations in Fumarate Hydratase in Multiple Cutaneous and Uterine Leiomyomatosis and Renal Cell Cancer

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

Melanoma and basal cell carcinoma in the hereditary leiomyomatosis and renal cell cancer syndrome. An expansion of the oncologic spectrum.

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