Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. 1276 Oct 39

Hereditary leiomyomatosis and renal cell cancer (HLRCC) (MIM 605839) is a recently identified autosomal dominant tumor susceptibility syndrome characterized by predisposition to benign leiomyomas of the skin and the uterus (fibroids, myomas). Susceptibility to early-onset renal cell carcinoma and uterine leiomyosarcoma is present in a subset of families. Renal cell carcinomas are typically solitary and aggressive tumors displaying papillary type 2 or collecting duct histology. The disease predisposing gene was identified as fumarate hydratase (fumarase, FH) (MIM 136850). FH encodes an enzyme that operates in the mitochondrial Krebs cycle being thus involved in cellular energy metabolism. The recent discovery of HLRCC and the predisposing gene FH has increased the present knowledge of hereditary renal cancer and enabled identification of the predisposed individuals. This review provides the present knowledge of the clinical, histopathological, and molecular features of HLRCC. Future prospects related to studies on the phenotype and molecular biology of HLRCC will also be discussed.
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PMID:Hereditary leiomyomatosis and renal cell cancer (HLRCC). 1557 34