title: Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer.
abstract: 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 A-site, 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 MCUL. That all missense FH mutations associating with MCUL/hereditary leiomyomatosis and renal cell cancer showed diminished FH enzymatic activity suggests that the tumor suppressor role of fumarate hydratase may relate to its enzymatic function.
authors.affiliation: Molecular and Population Genetics Laboratory, Cancer Research UK, Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: N Afrina
authors.initials: NA
authors.lastname: Alam
authors.forename: Simon
authors.initials: S
authors.lastname: Olpin
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowan
authors.forename: David
authors.initials: D
authors.lastname: Kelsell
authors.forename: Irene M
authors.initials: IM
authors.lastname: Leigh
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Todd
authors.initials: T
authors.lastname: Weaver
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005649:Fumarate Hydratase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D018231:Leiomyomatosis / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics*; D014594:Uterine Neoplasms / Q000201:enzymology / Q000235:genetics*
chemical_list: D005649:Fumarate Hydratase