Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency

Abstract

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.

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.…”

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

“…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.…”

“…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).…”

El espectro del carcinoma renal papilar

“…Aproximadamente el 30% de los pacientes con este síndrome desarrollan un único carcinoma renal de alto grado de malignidad histológicamente superponible al tipo 2 de carcinoma papilar renal 47 , aunque se han descrito casos morfológicamente superponibles al carcinoma de ductos colectores y oncocitomas. Se trata de tumores de alta agresividad biológica, con elevado índice de metástasis en el momento del diagnóstico.…”

“…Se trata de tumores de alta agresividad biológica, con elevado índice de metástasis en el momento del diagnóstico. El síndro-me se transmite de manera autosómica dominante y la alteración se localiza en 1q42.3-43 47 .…”