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PubMed1984

Purification, kinetic behavior, and regulation of NAD(P)+ malic enzyme of tumor mitochondria.

The purification and kinetic characterization of an NAD(P)+-malic enzyme from 22aH mouse hepatoma mitochondria are described. The enzyme was purified 328-fold with a final yield of 51% and specific activity of 38.1 units/mg of protein by employing DEAE-cellulose chromatography and an ATP affinity column. Sephadex G-200 chromatography yielded a native Mr = 240,000. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a major subunit with Mr = 61,000, suggesting a tetrameric structure, and also showed that the preparation contained less than 10% polypeptide impurities. Use of the ATP affinity column required the presence of MnCl2 and fumarate (an allosteric activator) in the elution buffers. In the absence of fumarate, the Michaelis constants for malate, NAD+, and NADP+ were 3.6 mM, 55 microM, and 72 microM, respectively; in the presence of fumarate (2 mM), the constants were 0.34 mM, 9 microM, and 13 microM, respectively. ATP was shown to be an allosteric inhibitor, competitive with malate. However, the inhibition by ATP displayed hyperbolic competitive kinetics with a KI (ATP) of 80 microM (minus fumarate) and 0.5 mM (plus 2 mM fumarate). The allosteric properties of the enzyme are integrated into a rationale for its specific role in the pathways of malate and glutamate oxidation in tumor mitochondria.

Animals↗
PubMed2000

Interventions for psoriatic arthritis.

OBJECTIVES: To assess the effects of salazopyrin, auranofin, etretinate, fumaric acid, IMI gold, azathioprine, and methotrexate, in psoriatic arthritis. SEARCH STRATEGY: We searched Medline up to 1995, and Excerpta Medica (June 1974-95). Search terms were psoriasis, arthritis, therapy and/or controlled trial. This was supplemented by manually searching bibliographies of previously published reviews, conference proceedings and contacting drug companies. All languages were included in the initial search. SELECTION CRITERIA: All randomized trials comparing salazopyrin, auranofin, etretinate, fumaric acid, IMI gold, azathioprine, and methotrexate, in psoriatic arthritis. The main outcome measures included individual component variables derived from Outcome Measures in Rheumatology Clinical Trials (OMERACT). These include Acute Phase Reactants, Disability, Pain, Patient Global Assessment, Physician Global Assessment, Swollen joint count, Tender joint count and radiographic changes of joints in any trial of 1 year or longer [Tugwell 1993], and the change in pooled disease index. Only English trials were included in the review. DATA COLLECTION AND ANALYSIS: Data were independently extracted from the published reports by two of the reviewers. An independent blinded quality assessment was also performed. MAIN RESULTS: Nineteen randomized trials were identified of which eleven were included in the quantitative analysis with data from 777 subjects. Although all agents were better than placebo, parenteral high dose methotrexate (not included), salazopyrin, azathioprine and etretinate were the agents that achieved statistical significance in a global index of disease activity (although it should be noted that only one component variable was available for azathioprine and only one trial was available for etretinate suggesting some caution is necessary in interpreting these results). Analysis of response in individual disease activity markers was more variable with considerable differences between different medications and responses. In all trials the placebo group improved over baseline (pooled improvement 0.43 DI units, 95% CI 0. 28-0.59). There was insufficient data to examine toxicity. REVIEWER'S CONCLUSIONS: Parenteral high dose methotrexate and salazopyrin are the only two agents with well demonstrated published efficacy in psoriatic arthritis. The magnitude of the effect seen with azathioprine, etretinate, oral low dose methotrexate and perhaps colchicine suggests that they may be effective but that further multicentre clinical trials are required to establish their efficacy. Furthermore, the magnitude of the improvement observed in the placebo group strongly suggests that uncontrolled trials should not be used to guide management decisions in this condition.

Antirheumatic Agents↗
PubMed2005

Production of L-malic acid by permeabilized cells of commercial Saccharomyces sp. strains.

Of various yeasts tested in the conversion of fumaric to L-malic acid, Saccharomyces bayanus had the highest activity of fumarase. Cells permeabilized with 0.2% (w/v) CTAB for 5 min gave maximum enzyme activity. Under non-growth conditions, fumarase activity in the permeabilized cells was four times higher (271 U/g) than that of the intact cells (67 U/g). The proposed mathematical model for the batch production of L-malic acid was validated at different initial fumaric acid concentrations. The average conversion of fumaric acid was up to 82% and gave 21, 40, 83 and 175 mM L-malic acid from respectively, 25, 50, 100 and 210 mM: fumaric acid.

Cell Membrane Permeability↗
PubMed2001

Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner.

Fumaric acid esters are thought to improve psoriasis by altering leukocyte, keratinocyte, and/or endothelial functions. To determine specificity, kinetics, and molecular mechanisms of different fumaric acid esters in their ability to inhibit endothelial cell activation, we analyzed CD62E and CD54 expression in endothelial cells in vivo and in vitro. In lesional skin of psoriatic patients, oral fumaric acid ester treatment resulted in a marked reduction of CD62E but not CD54 expression on dermal microvessels. Using human umbilical vein endothelial cells, dimethylfumarate almost completely inhibited tumor-necrosis-factor-induced CD62E, but not CD54 expression at concentrations < or = 70 microM, mimicking the situation in vivo. A 60 min dimethylfumarate preincubation was sufficient to block tumor-necrosis-factor-induced CD62E expression for up to 24 h. In contrast, equimolar concentrations of methylhydrogenfumarate, the hydrolysis product of dimethylfumarate, did not suppress tumor-necrosis-factor-induced CD62E expression. Likewise, all fumaric acid esters other than dimethylfumarate were ineffective. Using CD62E, NF-kappa B, or AP-1-responsive promoter constructs, dimethylfumarate inhibited tumor-necrosis-factor-induced activation of the CD62E and the NF-kappa B but not the AP-1 promoter construct. In summary, at a dose range < or = 70 microM, dimethylfumarate appeared to be a specific inhibitor of CD62E expression in an NF-kappa B-dependent manner.

Capillaries↗
PubMed2006

Synthesis of small tripeptide molecules through a catalysis sequence comprising metathesis and aminohydroxylation.

Tripeptidic structures were synthesized by using a combination of two independent consecutive catalytic procedures. Cross-metathesis of N-acroyl amino acid esters yields fumaric amide compounds with exclusive E double-bond geometry. This represents an unprecedented example of complete double-bond selectivity in this kind of reaction. A subsequent asymmetric aminohydroxylation of the chiral fumaric amides was carried out without the need of any further ligand and gave high yields and no side products. This reaction transforms the central fumaric amide unit into a hydroxy aspartic acid moiety and relies on the inherent stereochemistry of the starting fumaric diamides. An additional feature of our sequence is the ease of generating stereochemical diversification within the aminohydroxylation reaction. As a consequence, rapid conformational and configurational diversification can be achieved from the overall two-step catalytic sequence. The versatility of this approach is demonstrated by starting from two different N-acroyl amino esters, which led to the synthesis of eight structurally and stereochemically different tripeptides that could all be identified individually. As such, the present two-step catalytic approach should serve to efficiently synthesize large families of tripeptidic molecular probes.

Amides↗
PubMed1977

The functioning of cytochrome b in the electron transport to furmarate in Propionibacterium freudenreichii and Propionibacterium pentosaceum.

Fumarase-free electron particles from Propionibacterium freudenreichii and P. pentosaceum were prepared by discontinuous sucrose gradient centrifugation, and the influence of 2-n-heptyl-4-hydroxy-quinoline-N-oxide (HQNO) and ultraviolet irradiation on the reduction of menaquinone and cytochrome b with L-lactate or glycerol-3-phosphate and the reoxidation by fumarate was studied. In the presence of HQNO the steady state reduction level of menaquinone during fumarate reduction was increased whereas the steady state reduction level of cytochrome b was decreased as compared with the reduction levels measured in the absence of HQNO. The steady state reduction level of menaquinone during electron transport to fumarate was not influenced by ultraviolet irradiation and the steady state reduction level of cytochrome b was decreased at increasing irradiation times. The data indicate that cytochrome b is involved in the electron transport to fumarate.

Aerobiosis↗
PubMed2001

DctA- and Dcu-independent transport of succinate in Escherichia coli: contribution of diffusion and of alternative carriers.

Quintuple mutants of Escherichia coli deficient in the C(4)-dicarboxylate carriers of aerobic and anaerobic metabolism (DctA, DcuA, DcuB, DcuC, and the DcuC homolog DcuD, or the citrate/succinate antiporter CitT) showed only poor growth on succinate (or other C(4)-dicarboxylates) under oxic conditions. At acidic pH (pH 6) the mutants regained aerobic growth on succinate, but not on fumarate. Succinate uptake by the mutants could not be saturated at physiological succinate concentrations (< or =5 mM), in contrast to the wild-type, which had a K(m) for succinate of 50 microM and a V(max) of 35 U/g dry weight at pH 6. At high substrate concentrations, the mutants showed transport activities (32 U/g dry weight) comparable to that of the wild-type. In the wild-type using DctA as the carrier, succinate uptake had a pH optimum of 6, whereas succinate uptake in the mutants was maximal at pH 5. In the mutants succinate uptake was inhibited competitively by monocarboxylic acids. Diffusion of succinate or fumarate across phospholipid membranes (liposomes) was orders of magnitude slower than the transport in the wild-type or the mutants. The data suggest that mutants deficient in DctA, DcuA, DcuB, DcuC, DcuD (or CitT) contain a carrier, possibly a monocarboxylate carrier, which is able to transport succinate, but not fumarate, at acidic pH, when succinate is present as a monoanion. Succinate uptake by this carrier was inhibited by addition of an uncoupler. Growth by fumarate respiration (requiring fumarate/succinate antiport) was also lost in the quintuple mutants, and growth was not restored at pH 6. In contrast, the efflux of succinate produced during glucose fermentation was not affected in the mutants, demonstrating that, for succinate efflux, a carrier different from, or in addition to, the known Dcu and CitT carriers is used.

Bacterial Proteins↗
PubMed1983

Kinetic mechanism of bovine liver argininosuccinate lyase.

The kinetic mechanism of bovine liver argininosuccinate lyase has been determined at pH 7.5, 25 degrees C. Fumarate and arginine are both noncompetitive inhibitors versus argininosuccinate. The dead-end inhibitor, succinate, is competitive versus fumarate and argininosuccinate, but noncompetitive versus arginine. Citrulline is competitive versus arginine and noncompetitive versus argininosuccinate and fumarate. The results are consistent with a random mechanism with the formation of two dead-end complexes: E . argininosuccinate . fumarate and E . argininosuccinate . arginine. No evidence was obtained for nonlinear reciprocal plots. The equilibrium constant was found to be 3.7 mM.

Animals↗
PubMed1990

Fumarase: viscosity dependence of the kinetic parameters.

Fumarase catalyzes the reversible, stereospecific hydration of fumarate to form L-malate. We have determined the viscosity dependence of V/K and V in both the forward and the reverse directions at pH 6.9 in the absence and presence of several viscosogenic reagents. V/K for fumarate hydration decreases with increasing concentrations of glycerol and sucrose, but is unaffected by increasing concentrations of the polymeric viscosogen polyethyleneglycol (av MW, 10,000 da). V/K for malate dehydration similarly decreases with increasing concentrations of both glycerol and sucrose, but is unaffected by increasing concentrations of polyethylene glycol. Equilibrium constants, calculated from the ratio of V/K values for malate dehydration and fumarate hydration at various concentrations of glycerol, closely match the experimentally determined equilibrium constants at the same concentrations of glycerol. Both experimental and calculated equilibrium constants decrease with increasing concentrations of viscosogens. V/K for the dehydration of (-)-tartrate, a poor substrate, is unaffected by increasing concentrations of glycerol. Analysis of the microviscosity dependence of malate dehydration and fumarate hydration suggests that both substrates bind at diffusion-limited rates. The viscosity dependence of substrate and product dissociation steps may also contribute to the viscosity dependence of V/K values for both substrates. The viscosity dependence of the maximal velocities argues that product dissociation steps are rate-limiting and diffusion controlled.

Animals↗
PubMed1992

Characterization of the transport of tri- and dicarboxylates by pig intestinal brush-border membrane vesicles.

1. Transport of citrate and fumarate across the pig intestinal brush-border membrane (BBM) was investigated using isolated BBM vesicles. 2. Citrate and fumarate uptake was stimulated by an inwardly directed Na+ gradient consistent with Na+/citrate (fumarate) co-transport. Cis-inhibition and trans-stimulation experiments strongly suggest the existence of a common transport site for tri- and dicarboxylates. 3. The protonated forms of citrate (citrate-1, citrate-2) seem to be much better transported than citrate-3, indicated by the strong stimulation of citrate uptake at an extravesicular pH of 5.6 compared to pH 7.8. 4. Uptake of tri- and dicarboxylates seems to be potential-sensitive since citrate and in particular fumarate transport was enhanced by an inside negative potential difference. 5. Kinetics of succinate transport revealed a single carrier-mediated component with apparent kinetic constants of 0.43 nmol/mg protein-3 s (Vmax) and 0.14 mmol/l (Km).

Animals↗
PubMed2006

S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate.

S-(2-Succinyl)cysteine (2SC) has been identified as a chemical modification in plasma proteins, in the non-mercaptalbumin fraction of human plasma albumin, in human skin collagen, and in rat skeletal muscle proteins and urine. 2SC increases in human skin collagen with age and is increased in muscle protein of diabetic vs. control rats. The concentration of 2SC in skin collagen and muscle protein correlated strongly with that of the advanced glycation/lipoxidation end-product (AGE/ALE), N(epsilon)-(carboxymethyl)lysine (CML). 2SC is formed by a Michael addition reaction of cysteine sulfhydryl groups with fumarate at physiological pH. Fumarate, but not succinate, inactivates the sulfhydryl enzyme, glyceraldehyde-3-phosphate dehydrogenase in vitro, in concert with formation of 2SC. 2SC is the first example of spontaneous chemical modification of protein by a metabolic intermediate in the Krebs cycle. These observations identify fumarate as an endogenous electrophile and suggest a role for fumarate in regulation of metabolism.

Animals↗
PubMed1986

Genetic and physiological characterization of new Escherichia coli mutants impaired in hydrogenase activity.

The Mu dl (ApR lac) bacteriophage was used to generate mutants of Escherichia coli which were defective in formate hydrogenlyase. Three mutants were chosen for further analysis: they lacked hydrogenase (hydrogen: benzyl viologen oxidoreductase) activity, but produced normal levels of fumarate reductase activity and two- to three-fold reduced levels of benzyl viologen (BV)-dependent formate dehydrogenase activity. Two of them (hydC) were shown to contain about 4-fold reduced amounts of formate hydrogenlyase and fumarate-dependent H2 uptake activities. The third one (hydD) was totally devoid of both activities. Their insertion sites were located at 77 min on the E. coli map. Subdivision of these mutants into two classes was subsequently based on the restoration capacity of hydrogenase activity with high concentration of nickel in the growth media. Addition of 500 microM NiCl2 led to a complete recovery of hydrogenase activity, and to the concomitant restoration of normal BV-linked formate dehydrogenase, formate hydrogenlyase and fumarate-dependent H2 uptake activities in the hydC mutants. The hydD mutant was insensitive to the effect of nickel. Expression of the lac operon in hydC and hydD mutants was induced by anaerobiosis. It was not increased by the addition of formate under anaerobic conditions. The presence of nitrate resulted in slightly reduced beta-galactosidase activities in the hydC mutants, whereas those found in the hydD mutant reached only one third of the level obtained in its absence. Fumarate had no effect on both classes. Moreover, in contrast to the hydD locus, the hydC::Mu dl fusions were found to be dependent upon the positive control exerted by the nirR gene product and were totally repressed by an excess of nickel. In addition, the low levels of overall hydrogenase-dependent activities found in a nirR strain were also relieved by the presence of nickel. Our results strongly suggest that the pleiotropic regulatory gene nirR is essential for the expression of a gene (hydC) involved in either transport or processing of nickel in the cell, whose alteration leads to a loss of hydrogenase activity.

Alleles↗
PubMed1993

Role of conformational change in the fumarase reaction cycle.

Activation of fumarase by high concentrations of either malate or fumarate, often referred to as negative cooperativity, can be explained without assuming additional sites of substrate action or subunit-subunit interactions. The following observations support a model based on a rate-dependent recycling of free enzyme through a sequence of conformational states that differ in substrate specificity and catalytic activity: (1) Displacement from equilibrium of a radiolabeled malate/fumarate probe is readily induced by moderate concentrations of either substrate. This phenomenon, called substrate-induced countertransport, indicates that the steady-state ratio of free enzyme forms is very dependent on substrate concentration. (2) Related to this, the back-labeling that can be observed with either 14C product with either substrate in the steady state is more rapid than expected for a single free enzyme state model. (3) Fumarate, more strongly than malate, shows competitive effects as a product. This may reflect a higher affinity of fumarate for an isoform that also reacts with malate. (4) P(i), an activator of fumarase at midrange substrate concentration, overcomes strong competitive inhibition by fumarate of the M-->F reaction and increases recycling as shown by its effect on counterflow. To the extent that these effects are due to buffer activation, they suggest that proton transfer between solvent and the enzyme site is important in determining the recycling rate. (5) Transaconitate, a competitive inhibitor, overcomes counterflow induced by either substrate, indicating that recycling events occur in the enzyme-transaconitate complex.

Enzyme Activation↗
PubMed2003

The tetraheme cytochrome CymA is required for anaerobic respiration with dimethyl sulfoxide and nitrite in Shewanella oneidensis.

The tetraheme c-type cytochrome, CymA, from Shewanella oneidensis MR-1 has previously been shown to be required for respiration with Fe(III), nitrate, and fumarate [Myers, C. R., and Myers, J. M. (1997) J. Bacteriol. 179, 1143-1152]. It is located in the cytoplasmic membrane where the bulk of the protein is exposed to the periplasm, enabling it to transfer electrons to a series of redox partners. We have expressed and purified a soluble derivative of CymA (CymA(sol)) that lacks the N-terminal membrane anchor. We show here, by direct measurements of electron transfer between the purified proteins, that CymA(sol) efficiently reduces S. oneidensis fumarate reductase. This indicates that no further proteins are required for electron transfer between the quinone pool and fumarate if we assume direct reduction of CymA by quinols. By expressing CymA(sol) in a mutant lacking CymA, we have shown that this soluble form of the protein can complement the defect in fumarate respiration. We also demonstrate that CymA is essential for growth with DMSO (dimethyl sulfoxide) and for reduction of nitrite, implicating CymA in at least five different electron transfer pathways in Shewanella.

Amino Acid Sequence↗
PubMed2005

Functional roles of ATP-binding residues in the catalytic site of human mitochondrial NAD(P)+-dependent malic enzyme.

Human mitochondrial NAD(P)+-dependent malic enzyme is inhibited by ATP. The X-ray crystal structures have revealed that two ATP molecules occupy both the active and exo site of the enzyme, suggesting that ATP might act as an allosteric inhibitor of the enzyme. However, mutagenesis studies and kinetic evidences indicated that the catalytic activity of the enzyme is inhibited by ATP through a competitive inhibition mechanism in the active site and not in the exo site. Three amino acid residues, Arg165, Asn259, and Glu314, which are hydrogen-bonded with NAD+ or ATP, are chosen to characterize their possible roles on the inhibitory effect of ATP for the enzyme. Our kinetic data clearly demonstrate that Arg165 is essential for catalysis. The R165A enzyme had very low enzyme activity, and it was only slightly inhibited by ATP and not activated by fumarate. The values of K(m,NAD) and K(i,ATP) to both NAD+ and malate were elevated. Elimination of the guanidino side chain of R165 made the enzyme defective on the binding of NAD+ and ATP, and it caused the charge imbalance in the active site. These effects possibly caused the enzyme to malfunction on its catalytic power. The N259A enzyme was less inhibited by ATP but could be fully activated by fumarate at a similar extent compared with the wild-type enzyme. For the N259A enzyme, the value of K(i,ATP) to NAD+ but not to malate was elevated, indicating that the hydrogen bonding between ATP and the amide side chain of this residue is important for the binding stability of ATP. Removal of this side chain did not cause any harmful effect on the fumarate-induced activation of the enzyme. The E314A enzyme, however, was severely inhibited by ATP and only slightly activated by fumarate. The values of K(m,malate), K(m,NAD), and K(i,ATP) to both NAD+ and malate for E314A were reduced to about 2-7-folds compared with those of the wild-type enzyme. It can be concluded that mutation of Glu314 to Ala eliminated the repulsive effects between Glu314 and malate, NAD+, or ATP, and thus the binding affinities of malate, NAD+, and ATP in the active site of the enzyme were enhanced.

Adenosine Triphosphate↗
PubMed1966

Studies on the biochemistry of Penicillium charlesii. Influence of various dicarboxylic acids on galactocarolose synthesis.

1. It has been shown that Penicillium charlesii continues to synthesize galactocarolose when l-malic acid, malonic acid, succinic acid, fumaric acid, maleic acid or oxaloglycollic acid is substituted for dl-tartaric acid in the Raulin-Thom nutrient medium. 2. The quantity of galactocarolose synthesized per g. of mycelia was markedly decreased by substitution of l-malic acid, malonic acid, succinic acid, fumaric acid or maleic acid for dl-tartaric acid. Substitution of oxaloglycollic acid for dl-tartaric acid did not depress the galactocarolose synthesized/g. of mycelia; however, the quantity of fungal mass formed was decreased approximately fivefold. 3. Based upon (14)C incorporation into galactocarolose, succinic acid, fumaric acid or malonic acid did not serve as direct precursors of galactose as did tartaric acid. Oxaloglycollic acid, l-malic acid and maleic acid were not tested. 4. The relative quantity of galactocarolose synthesized per g. of mycelia decreased as the concentration of diammonium dicarboxylate added to the growth medium was increased. Tartaric acid, oxaloglycollic acid, fumaric acid and malonic acid were tested. 5. The quantity of mycelia formed and the quantity of galactocarolose synthesized per g. of mycelia were greater when the growth medium contained l-tartrate than when it contained d-tartrate.

Carbon Isotopes↗
PubMed2004

Identification of 42 possible cytochrome C genes in the Shewanella oneidensis genome and characterization of six soluble cytochromes.

Through pattern matching of the cytochrome c heme-binding site (CXXCH) against the genome sequence of Shewanella oneidensis MR-1, we identified 42 possible cytochrome c genes (27 of which should be soluble) out of a total of 4758. However, we found only six soluble cytochromes c in extracts of S. oneidensis grown under several different conditions: (1) a small tetraheme cytochrome c, (2) a tetraheme flavocytochrome c-fumarate reductase, (3) a diheme cytochrome c4, (4) a monoheme cytochrome c5, (5) a monoheme cytochrome c', and (6) a diheme bacterial cytochrome c peroxidase. These cytochromes were identified either through N-terminal or complete amino acid sequence determination combined with mass spectroscopy. All six cytochromes were about 10-fold more abundant when cells were grown at low than at high aeration, whereas the flavocytochrome c-fumarate reductase was specifically induced by anaerobic growth on fumarate. When adjusted for the different heme content, the monoheme cytochrome c5 is as abundant as are the small tetraheme cytochrome and the tetraheme fumarate reductase. Published results on regulation of cytochromes from DNA microarrays and 2D-PAGE differ somewhat from our results, emphasizing the importance of multifaceted analyses in proteomics.

Amino Acid Sequence↗
PubMed2005

Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer.

Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition that results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer syndrome in which affected individuals may develop the rare type II papillary renal cell cancer, in addition to skin leiomyomas. Recently, heterozygous mutations in the gene encoding fumarate hydratase have been found to underlie both conditions. Fumarate hydratase is an enzyme that catalyses the conversion of fumarate to malate in the Kreb's cycle and may also function as a tumour suppressor gene. We report a family with multiple leiomyomas, uterine fibroids and papillary renal cell cancer. The proband is a 77-year-old Polish woman who developed multiple cutaneous leiomyomas on her right upper arm in her thirties and subsequently underwent a hysterectomy for uterine fibroids in her forties. She has four offspring: her eldest daughter also has skin and uterine leiomyomas with a similar onset; her son has multiple skin leiomyomas and in addition was diagnosed with metastatic papillary renal cell cancer at the age of 50 years; the two youngest daughters are unaffected. DNA sequencing in all the affected individuals disclosed a heterozygous G-->C substitution at nucleotide 173 of the fumarate hydratase gene, that converts an arginine residue (CGA) to proline (CCA). This missense mutation has not been reported previously and is designated R58P. Interestingly, the clinically asymptomatic 20-year-old son of the individual with renal cancer was also found to be heterozygous for R58P. It is likely that he will develop skin leiomyomas in the future but the risk of renal cancer is difficult to predict. Nevertheless, detection of this mutation has important implications for screening and genetic counselling in this and other family members.

Aged↗