Dataset Information

The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency.

ABSTRACT: BACKGROUND:Fumarate hydratase (HGNC approved gene symbol - FH), also known as fumarase, is an enzyme of the tricarboxylic acid (TCA) cycle, involved in fundamental cellular energy production. First described by Zinn et al in 1986, deficiency of FH results in early onset, severe encephalopathy. In 2002, the Multiple Leiomyoma Consortium identified heterozygous germline mutations of FH in patients with multiple cutaneous and uterine leiomyomas, (MCUL: OMIM 150800). In some families renal cell cancer also forms a component of the complex and as such has been described as hereditary leiomyomatosis and renal cell cancer (HLRCC: OMIM 605839). The identification of FH as a tumor suppressor was an unexpected finding and following the identification of subunits of succinate dehydrogenase in 2000 and 2001, was only the second description of the involvement of an enzyme of intermediary metabolism in tumorigenesis. DESCRIPTION:The FH mutation database is a part of the TCA cycle gene mutation database (formerly the succinate dehydrogenase gene mutation database) and is based on the Leiden Open (source) Variation Database (LOVD) system. The variants included in the database were derived from the published literature and annotated to conform to current mutation nomenclature. The FH database applies HGVS nomenclature guidelines, and will assist researchers in applying these guidelines when directly submitting new sequence variants online. Since the first molecular characterization of an FH mutation by Bourgeron et al in 1994, a series of reports of both FH deficiency patients and patients with MCUL/HLRRC have described 107 variants, of which 93 are thought to be pathogenic. The most common type of mutation is missense (57%), followed by frameshifts & nonsense (27%), and diverse deletions, insertions and duplications. Here we introduce an online database detailing all reported FH sequence variants. CONCLUSION:The FH mutation database strives to systematically unify all current genetic knowledge of FH variants. We believe that this knowledge will assist clinical geneticists and treating physicians when advising patients and their families, will provide a rapid and convenient resource for research scientists, and may eventually assist in gaining novel insights into FH and its related clinical syndromes.

SUBMITTER: Bayley JP

PROVIDER: S-EPMC2322961 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency.

Bayley Jean-Pierre JP Launonen Virpi V Tomlinson Ian P M IP

BMC medical genetics 20080325

<h4>Background</h4>Fumarate hydratase (HGNC approved gene symbol - FH), also known as fumarase, is an enzyme of the tricarboxylic acid (TCA) cycle, involved in fundamental cellular energy production. First described by Zinn et al in 1986, deficiency of FH results in early onset, severe encephalopathy. In 2002, the Multiple Leiomyoma Consortium identified heterozygous germline mutations of FH in patients with multiple cutaneous and uterine leiomyomas, (MCUL: OMIM 150800). In some families renal c ...[more]

PMID: 18366737

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Project description:The role of energy deregulation and altered/adapted metabolism in tumor cells is an increasingly important issue in understanding cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive form of RCC characterized by germline mutation of fumarate hydratase (FH), followed by somatic loss of the remaining wild-type allele and known to be a highly metastatic and lethal malignancy compared to other RCCs. The intrinsic loss of normal tricarboxylic acid (TCA) cycle presumably aids tumorigenesis due to the necessary metabolic alterations required and the enforced dependence on glycolysis derived energy, mimicking the Warburg effect. Thus, there is considerable utility in establishing a preclinical cell model from these tumors to study energy metabolism deregulation, as well as developing new targeted therapeutic approaches for TCA cycle enzyme-deficient cancers. Here, we describe a new immortalized cell line, UOK268, derived from a patient's primary HLRCC-associated kidney cancer. This represents the first primary renal cell line to model TCA cycle gene loss and provides a perfect partner cell line to our previously described metastasis-derived HLRCC-associated cell line, UOK262. We identified a novel germline FH missense mutation, p.His192Asp, and the subsequent loss of heterozygosity in UOK268. The UOK268 cell line expressed mutant FH protein, which localized to the mitochondria, but with loss of almost all catalytic activity. The UOK268 cells had severely compromised oxidative phosphorylation and increased glycolytic flux. Ingenuity pathways analysis of human mitochondria-focused cDNA microarray (hMitChip3) gene chip data confirmed the altered mRNA expression patterns of genes involved in several important pathways, such as lipid metabolism, apoptosis, and energy production/glycolysis. UOK268 provides a unique model of a primary cell line demonstrating an enforced, irreversible Warburg effect and, combined with UOK262, provides a unique in vitro preclinical model for studying the bioenergetics of the Warburg effect in human cancer.

Dataset Information

The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency.

Publications

The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency.

Similar Datasets

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