| *136850 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FUMARATE HYDRATASE; FH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FUMARASE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FUMARATE HYDRATASE, CYTOSOLIC, INCLUDED; FH1, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FUMARATE HYDRATASE, MITOCHONDRIAL, INCLUDED; FH2, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: FH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 1q43 Genomic coordinates (GRCh37): 1:241,660,856 - 241,683,084 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fumarate hydratase, or fumarase (EC 4.2.1.2), is an enzymatic component of the tricarboxylic acid, or Krebs, cycle. It catalyzes the conversion of fumarate to malate. Enzyme Structure Fumarase exists in both cytosolic and mitochondrial forms, which differ in electrophoretic mobility. Kinsella and Doonan (1986) found an unusually high degree of identity of structure of human fumarase and that from B. subtilis and E. coli. Using peptide mapping, O'Hare and Doonan (1985) showed that the cytosolic and mitochondrial fumarases from pig liver are identical over nearly all of their amino acid sequences, but that they differ at their N-termini. Isoenzymes Edwards and Hopkinson (1979) studied a family with an electrophoretic variant of FH. Two persons had variation in both the soluble and the mitochondrial forms, suggesting that they are determined by a single locus. Posttranslational processing may account for the differences between the 2 forms. Another possibility is that the 2 enzymes are heteromeric and share a subunit coded by chromosome 1. If posttranslational processing is the mechanism, all control of processing (e.g., enzymes) seems to be coded by chromosome 1. Common genetic control of both soluble and mitochondrial fumarate hydratase is further supported by the finding of combined deficiency. Doonan et al. (1984) cited evidence suggesting that the isoenzymes of fumarase are translated in precursor form from 2 different mRNA molecules, these mRNAs in turn arising from alternative splicing of a single gene transcript. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Van Someren et al. (1974) and Craig et al. (1976) found that the fumarase locus is on chromosome 1, possibly in the area 1q42. Despoisses et al. (1984) narrowed the regional assignment of FH to 1q42.1 by gene dosage studies in patients with various types of partial trisomy or partial monosomy of 1q. Coughlin et al. (1993) mapped the FH gene to chromosome 1 using PCR-amplified cDNA as a probe in Southern blots of genomic DNA from a series of mouse/human somatic cell hybrids. They observed related sequences on chromosomes 13 and 5. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pollard et al. (2005) stated that the nuclear-encoded Krebs cycle enzymes fumarate hydratase and succinate dehydrogenases (see, e.g., SDHB 185470) act as tumor suppressors, and germline mutations in these genes predispose individuals to leiomyomas and renal cancer and to paragangliomas (see 115310), respectively. Pollard et al. (2005) showed that FH-deficient cells and tumors accumulated fumarate and, to a lesser extent, succinate. SDH-deficient tumors principally accumulated succinate. In situ analysis showed that these tumors also overexpressed HIF1A (603348), activation of HIF1A targets like VEGF (192240), and high microvessel density. Pollard et al. (2005) hypothesized that increased succinate and/or fumarate may stabilize HIF1A, and that the basic mechanism of tumorigenesis in paragangliomas and leiomyoma and renal cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau syndrome (193300). Using genetically modified mouse kidney cells in which Fh1 had been deleted, Frezza et al. (2011) applied a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of heme, enables Fh1-deficient cells to use accumulated tricarboxylic acid (TCA) cycle metabolites and permits partial mitochondrial NADH production. Frezza et al. (2011) predicted and confirmed that targeting this pathway would render Fh1-deficient cells nonviable, while sparing wildtype Fh1-containing cells. Frezza et al. (2011) concluded that their work went beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of heme oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a potential target for treating HLRCC (150800) patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In patients with fumarase deficiency (606812), Bourgeron et al. (1993) and Coughlin et al. (1993) identified mutations in the FH gene (136850.0001 and 136850.0002). In patients with multiple cutaneous and uterine leiomyomata (150800), Tomlinson et al. (2002) identified mutations in the FH gene (136850.0003 and 136850.0004). In patients with hereditary leiomyomatosis and renal cell cancer, Tomlinson et al. (2002) identified several mutations in the FH gene (136850.0005 and 136850.0006). Using sequence analysis, Toro et al. (2003) identified germline mutations in the FH gene in 31 of 35 (89%) families with cutaneous leiomyomas. Eighteen of the 20 different mutations they identified-- 2 insertions, 5 small deletions that caused frameshifts leading to premature truncation of the protein, and 13 missense--were novel. The same mutation, arg190 to his (R190H; 136850.0007), was identified in 11 unrelated families. Cutaneous leiomyomas were found in 81 individuals (47 women and 34 men). Uterine leiomyomas were also found in 98% (46 of 47) of women with cutaneous leiomyomas. Total hysterectomy was performed in 89% (41 of 46) of women with cutaneous and uterine leiomyomas, 44% before or at age 30 years. In 13 individuals in 5 families, Toro et al. (2003) identified unilateral and solitary renal tumors. Papillary type II renal cell carcinoma was present in 7 individuals from 4 families, and another individual from 1 of these families had collecting duct carcinoma of the kidney. The study expanded the histologic spectrum of renal tumors and FH mutations associated with hereditary leiomyomatosis and renal cell carcinoma. Barker et al. (2002) analyzed a series of 26 leiomyosarcomas and 129 uterine leiomyomas (from 21 patients) for somatic mutations in fumarate hydratase and allelic imbalance around 1q43. None of the 26 leiomyosarcomas harbored somatic mutations in fumarate hydratase. Only 5% (7 of 129) of the leiomyomas showed allele imbalance at 1q42-q43, and no somatic mutations in fumarate hydratase were observed. Alam et al. (2003) reported 20 FH mutations in 35 of 46 probands with multiple cutaneous and uterine leiomyomata (MCUL) or FH deficiency. Disease-associated missense FH changes mapped to highly conserved residues, mostly in or around the enzyme's active site or activation site. The mutation spectra in FH deficiency and MCUL were similar, although in the latter mutations tended to occur more 5-prime in the gene and were predicted to result in a truncated or absent protein. The authors reported that not all mutation-carrier parents of FH deficiency children had a strong predisposition to leiomyomata. Renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome; these cancers may have either type II papillary or collecting duct morphology. There was 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 may indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. The authors concluded that MCUL is probably a genetically homogeneous tumor predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity. To determine whether FH mutations may predispose women to developing nonsyndromic uterine leiomyomas (UL; 150669), Gross et al. (2004) performed a genetic linkage study with DNA from 123 families containing at least 1 affected sister pair. In addition, to assess the frequency of FH loss specifically in uterine leiomyomas with 1q rearrangements, they performed a FISH analysis of UL. Analysis of the genotyping data revealed evidence suggestive of linkage to the FH region among study participants who were less than 40 years of age at diagnosis (p = 0.04). FISH results showed that 1 copy of FH was absent in 9 of 11 ULs. Gross et al. (2004) concluded that loss of FH may be a significant event in the pathogenesis of a subset of nonsyndromic ULs. Because some individuals with HLRCC with a germline FH mutation have breast cancer (114480), Kiuru et al. (2005) analyzed germline FH mutations from 85 Finnish breast cancer patients, most of whom were selected based on positive family or personal history for malignancies associated with HLRCC. No mutations were found. Kiuru et al. (2005) concluded that FH is not a major predisposing gene for familial breast cancer. Wei et al. (2006) identified 14 mutations in the FH gene, including 9 novel mutations, in affected members of 13 families with HLRCC and 8 families with multiple cutaneous and uterine leiomyomata. Four unrelated families had the R58X mutation (136850.0003) and 5 unrelated families had the R190H mutation (136850.0007). Cutaneous leiomyomata were present in 16 (76%) of 21 families, ranging from mild to severe. All 22 female mutation carriers from 16 families had uterine fibroids. Renal tumors occurred in 13 (62%) of 21 families. No genotype/phenotype correlations were identified. To examine the cancer risk and tumor spectrum in Finnish families positive for FH mutations, Lehtonen et al. (2006) collected genealogic and cancer data from 868 individuals. FH mutation status was analyzed in all 98 available patients. The standardized incidence ratio (SIR) was 6.5 for renal cell carcinoma (RCC) and 71 for uterine leiomyosarcoma (ULMS). The overall cancer risk was statistically significantly increased in the age group of 15 to 29 years, consistent with features of cancer predisposition families in general. An FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, Lehtonen et al. (2006) observed several benign tumors including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas. As part of the French National Cancer Institute study, Gardie et al. (2011) identified 32 different heterozygous germline mutations in the FH gene, including 21 novel mutations, in 40 (71.4%) of 56 families with proven HLRCC. In addition, FH mutations were found in 4 (17.4%) of 23 probands with isolated type 2 papillary renal cell carcinoma, including 2 patients with no family history. In vitro functional expression studies showed that all mutations caused about a 50% decrease in FH enzymatic activity. In addition, there were 5 asymptomatic mutation carriers in 3 families, indicating incomplete penetrance. The findings indicated that renal call carcinoma can be the only manifestation of this disorder. No genotype/phenotype correlations were identified. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 FUMARASE DEFICIENCY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, ALA265THR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient of Arab ancestry with fumarase-deficiency (606812), Coughlin et al. (1993) identified a G-to-A transition at nucleotide 793 changing ala265 to thr (A265T). The father was shown to be heterozygous for the mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 FUMARASE DEFICIENCY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, GLU319GLN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bourgeron et al. (1993, 1994) described a glu319-to-gln (E319Q) mutation in the FH gene in 2 daughters of first-cousin Moroccan parents who presented with progressive encephalopathy, dystonia, leukopenia, and neutropenia at an early age. Elevation of lactate in the cerebrospinal fluid (so-called hyperlactatorachia) and high fumarate excretion in the urine led Bourgeron et al. (1994) to investigate the activities of the respiratory chain and of the Krebs cycle, and finally to identify fumarase deficiency (606812). The deficiency was profound, was present in all tissues investigated, and affected the cytosolic and mitochondrial isoenzymes to the same degree. The sibs were homozygous for a missense mutation, a G-to-C transversion at nucleotide 955. The predicted amino acid substitution occurred in a highly conserved region of the fumarase cDNA. Both parents exhibited half the expected fumarase activity in their lymphocytes and were found to be heterozygous for the mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, ARG58TER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 3 families, Tomlinson et al. (2002) found that members affected by multiple cutaneous and uterine leiomyomata (150800) had a change of codon 58 from CGA (arg) to TGA (stop) (R58X) in exon 2 of the FH gene. In 3 unrelated families with hereditary leiomyomatosis and renal cell cancer, Wei et al. (2006) identified the R58X mutation, resulting from a 172C-T transition. The R58X mutation was also identified in affected members of a fourth unrelated family with multiple cutaneous and uterine leiomyomata. Haplotype analysis of the families did not show a founder effect, suggesting that R58X represents a hot spot mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, ASN64THR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 6 separate families, Tomlinson et al. (2002) found that individuals with multiple cutaneous and uterine leiomyomata (150800) were heterozygous for a mutation in codon 64 in exon 2 of the FH gene converting AAC (asn) to ACC (thr) (N64T). In a 55-year-old man with hereditary leiomyomatosis and renal cell cancer and the N64T mutation in the FH gene, Carvajal-Carmona et al. (2006) identified a Leydig cell tumor of the testis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, 2-BP DEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 Finnish families with the hereditary leiomyomatosis and renal cell cancer syndrome (150800), Tomlinson et al. (2002) found a 2-bp deletion in codon 181 in exon 4 of the FH gene: conversion of GAGTTT to GTTT. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, ARG300TER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Finnish family with the hereditary leiomyomatosis and renal cell cancer syndrome (150800), Tomlinson et al. (2002) found a nonsense mutation converting codon 300 in exon 6 of the FH gene from CGA (arg) to TGA (stop) (R300X). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, ARG190HIS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 4 individuals from a family with cutaneous and uterine leiomyomatosis and renal cell cancer (HLRCC; 150800), Toro et al. (2003) identified a 569G-A transition in exon 4 of the FH gene, resulting in an arg190-to-his (R190H) mutation. The R190H mutation was also present in 10 other unrelated families with cutaneous and uterine leiomyomatosis, but screening for occult renal tumors in affected individuals from these 10 families did not identify renal tumors. Thus there appeared to be other genetic and/or environmental factors that influenced the phenotype. Wei et al. (2006) identified the R190H mutation in affected members of 3 unrelated families with HLRCC. The R190H mutation was also identified in affected members of 2 additional families with multiple cutaneous and uterine leiomyomata. A founder effect could not be determined. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, ARG190LEU | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Toro et al. (2003) described a family with leiomyomatosis and renal cell cancer (150800) associated with a 569G-T transition in exon 4 of the FH gene, resulting in an arg190-to-leu (R190L) mutation. The nucleotide substitution occurred at the same position as that changed in the common R190H mutation (136850.0007). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FH, ARG58PRO [dbSNP:rs75086406] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a family with multiple cutaneous and uterine leiomyomata (150800), Chan et al. (2005) identified a heterozygous 173G-C transversion in exon 3 of the FH gene, resulting in an arg58-to-pro (R58P) substitution. The proband was a 77-year-old Polish woman with multiple cutaneous leiomyomas and uterine fibroids. Her eldest daughter had a similar phenotype, and 2 unaffected daughters did not have the mutation. Her son had multiple skin leiomyomas and was diagnosed with metastatic papillary renal cell cancer at age 50 years, and his asymptomatic 20-year-old son was also found to carry the mutation and was thus likely to develop skin leiomyomas, but the risk of renal cancer was difficult to predict. Chan et al. (2005) noted that a nonsense mutation in the same residue had been reported (R58X; 136850.0003). Heinritz et al. (2008) identified the R58P mutation in affected members of a large German family with multiple cutaneous and uterine leiomyomata without renal cancer. Family history revealed that this German family originally came from Poland but was dispersed after World War II. Haplotype analysis of this family and that reported by Chan et al. (2005) demonstrated a founder effect for the mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Busby et al. (1976); Edwards and Hopkinson (1979); Petrova-Benedict et al. (1987); Tolley and Craig (1975); van Someren et al. (1974) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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