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JMD 2005, Vol. 7, No. 4
Copyright © 2005 American Society for Investigative Pathology & Association for Molecular Pathology

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

N. Afrina Alam^*, Simon Olpin, Andrew Rowan^*, David Kelsell, Irene M. Leigh, Ian P. M. Tomlinson^* and Todd Weaver

From the Molecular and Population Genetics Laboratory, * Cancer Research UK, London, United Kingdom; The Centre for Cutaneous Research, St. Bartholomew’s and London School of Medicine and Dentistry, Queen Mary and Westfield College, London, United Kingdom; The Department of Clinical Biochemistry, Sheffield Children’s Hospital, Sheffield, United Kingdom; and the Department of Chemistry, University of Wisconsin–La Crosse, La Crosse, Wisconsin

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.