Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America

Abstract

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.

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

“…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).…”

“…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).…”

“…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.…”

“…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.…”

Smooth muscle tumors of soft tissue and non-uterine viscera: biology and prognosis

“…This is coupled with a somatic loss of the other allele of FH in the tumor cells, and therefore FH behaves as a classic tumor suppressor gene, with bi-allelic inactivation causing the disease. [14][15][16] Most HLRCC patients develop coalescent clusters and streaks of multiple pilar leiomyomas in the extremities or trunk at a relatively young age. Some tumors have atypical features by the presence of nuclear atypia and even some mitotic activity, but truly malignant behavior does not seem to be a clinical problem.…”