Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertrophic cardiomyopathy is associated with marked genetic and phenotypic heterogeneity. Pathogenic mutations in the 10 hypertrophic cardiomyopathy-associated sarcomeric genes cause autosomal dominant disease as a rule, although recessive disease has been reported. Cardiac hypertrophy is also a hallmark of Friedreich ataxia, an autosomal recessive disease caused by deficiency of the mitochondrial protein frataxin. We hypothesized that heterozygous mutations in frataxin may mimic or modify hypertrophic cardiomyopathy. Using DHPLC and DNA sequencing, we identified the novel R40C-frataxin mutation in a patient who also harbored a previously reported R810H-myosin binding protein C mutation. The R810H mutation is reported to cause hypertrophic cardiomyopathy only in the setting of homozygosity or compound heterozygosity with another sarcomeric mutation. Site-directed mutagenesis and in vitro and in vivo analysis enabled functional characterization of the mutant frataxin protein. R40C-frataxin protein is not cleaved to the mature form in vitro and shows delayed kinetics of cleavage by isolated mouse mitochondria. Yeast cells expressing R40C-frataxin demonstrated increased sensitivity to oxidative stress and abnormal accumulation of precursor frataxin protein. These data indicate that frataxin deficiency may have contributed to this patient's particular phenotype. Furthermore, these findings suggest that mutations altering myocyte energetics may act in synergy with sarcomeric mutations to cause hypertrophic cardiomyopathy.
Mol Genet Metab 2005 Aug
PMID:Molecular and functional characterization of a human frataxin mutation found in hypertrophic cardiomyopathy. 1593 68

Frataxin deficiency is the main cause of Friedreich ataxia, an autosomal recessive neurodegenerative disorder. Frataxin function in mitochondria has not been fully explained yet. In this work, we show that Saccharomyces cerevisiae frataxin orthologue Yfh1p interacts physically with succinate dehydrogenase complex subunits Sdh1p and Sdh2p of the yeast mitochondrial electron transport chain and also with electron transfer flavoprotein complex ETFalpha and ETFbeta subunits from the electron transfer flavoprotein complex. Genetic synthetic interaction experiments confirmed a functional relationship between YFH1 and succinate dehydrogenase genes SDH1 and SDH2. We also demonstrate a physical interaction between human frataxin and human succinate dehydrogenase complex subunits, suggesting also a key role of frataxin in the mitochondrial electron transport chain in humans. Consequently, we suggest a direct participation of the respiratory chain in the pathogenesis of the Friedreich ataxia, which we propose to be considered as an OXPHOS disease.
Hum Mol Genet 2005 Aug 01
PMID:Frataxin interacts functionally with mitochondrial electron transport chain proteins. 1596 14

The mitochondrial iron chaperone, frataxin, plays a critical role in cellular iron homeostasis and the synthesis and regeneration of Fe-S centers. Genetic insufficiency for frataxin is associated with Friedreich's Ataxia in humans and confers loss of function of Fe-containing proteins including components of the respiratory chain and mitochondrial and cytosolic aconitases. Here, we report the use of RNA-interference (RNAi) to suppress frataxin in the multicellular eukaryote, Drosophila. Phenotypically, suppression of the Drosophila frataxin homologue (dfh) confers distinct phenotypes in larvae and adults, leading to giant long-lived larvae and to conditional short-lived adults. Deficiency of the DFH protein results in diminished activities of numerous heme- and iron-sulfur-containing enzymes, loss of intracellular iron homeostasis and increased susceptibility to iron toxicity. In parallel with the differential larval and adult phenotypes, our results indicate that dfh silencing differentially dysregulates ferritin expression in adults but not in larvae. Moreover, silencing of dfh in the peripheral nervous system, a specific focus of Friedreich's pathology, permits normal larval development but imposes a marked reduction in adult lifespan. In contrast, dfh silencing in motorneurons has no deleterious effect in either larvae or adults. Finally, overexpression of Sod1, Sod2 or Cat does not suppress the failure of DFH-deficient animals to successfully complete eclosion, suggesting a minimal role of oxidative stress in this phenotype. The robust developmental, biochemical and tissue-specific phenotypes conferred by DFH deficiency in Drosophila provide a platform for identifying genetic, nutritional and environmental factors, which ameliorate the symptoms arising from frataxin deficiency.
Hum Mol Genet 2005 Nov 15
PMID:RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila. 1620 42

Deficiency of the frataxin mRNA alters the transcriptome, triggering neuro- and cardiodegeneration in Friedreich's ataxia. We microarrayed murine frataxin-deficient heart tissue, liver tissue and cardiocytes and observed a transcript down-regulation to up-regulation ratio of nearly 2:1 with a mitochondrial localization of transcriptional changes. Combining all mouse and human microarray data for frataxin-deficient cells and tissues, the most consistently decreased transcripts were mitochondrial coproporphyrinogen oxidase (CPOX) of the heme pathway and mature T-cell proliferation 1, a homolog of yeast COX23, which is thought to function as a mitochondrial metallochaperone. Quantitative RT-PCR studies confirmed the significant down-regulation of Isu1, CPOX and ferrochelatase at 10 weeks in mouse hearts. We observed that mutant cells were resistant to aminolevulinate-dependent toxicity, as expected if the heme pathway was inhibited. Consistent with this, we observed increased cellular protoporphyrin IX levels, reduced mitochondrial heme a and heme c levels and reduced activity of cytochrome oxidase, suggesting a defect between protoporphyrin IX and heme a. Fe-chelatase activities were similar in mutants and controls, whereas Zn-chelatase activities were slightly elevated in mutants, supporting the idea of an altered metal-specificity of ferrochelatase. These results suggest that frataxin deficiency causes defects late in the heme pathway. As ataxic symptoms occur in other diseases of heme deficiency, the heme defect we observe in frataxin-deficient cells could be primary to the pathophysiological process.
Hum Mol Genet 2005 Dec 15
PMID:Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. 1623 44

Friedreich ataxia is a severe autosomal-recessive disease characterized by neurodegeneration, cardiomyopathy and diabetes, resulting from reduced synthesis of the mitochondrial protein frataxin. Although frataxin is ubiquitously expressed, frataxin deficiency leads to a selective loss of dorsal root ganglia neurons, cardiomyocytes and pancreatic beta cells. How frataxin normally promotes survival of these particular cells is the subject of intense debate. The predominant view is that frataxin sustains mitochondrial energy production and other cellular functions by providing iron for heme synthesis and iron-sulfur cluster (ISC) assembly and repair. We have proposed that frataxin not only promotes the biogenesis of iron-containing enzymes, but also detoxifies surplus iron thereby affording a critical anti-oxidant mechanism. These two functions have been difficult to tease apart, however, and the physiologic role of iron detoxification by frataxin has not yet been demonstrated in vivo. Here, we describe mutations that specifically impair the ferroxidation or mineralization activity of yeast frataxin, which are necessary for iron detoxification but do not affect the iron chaperone function of the protein. These mutations increase the sensitivity of yeast cells to oxidative stress, shortening chronological life span and precluding survival in the absence of the anti-oxidant enzyme superoxide dismutase. Thus, the role of frataxin is not limited to promoting ISC assembly or heme synthesis. Iron detoxification is another function of frataxin relevant to anti-oxidant defense and cell longevity that could play a critical role in the metabolically demanding environment of non-dividing neuronal, cardiac and pancreatic beta cells.
Hum Mol Genet 2006 Feb 01
PMID:Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. 1637 22

Triplet repeat expansions were first discovered in 1991 and since then have been found to be the mutation underlying a range of neurodegenerative, neuromuscular, and cognitive disorders including fragile X syndrome, myotonic dystrophy, Friedreich's ataxia, and the polyglutamine disorders that include Huntington's disease. The repeats exert their detrimental effects through different molecular mechanisms dependent on whether they are located in coding or noncoding regions of the gene in question. During the past 10 yr, a wide range of strategies have been used to successfully establish mouse models for all of these disorders. This review presents an overview of these mouse models, discusses the insights into the molecular pathogenesis of these disorders that have been gained from their analysis and the strategies that are being used to uncover novel therapeutic options.
Mol Biotechnol 2006 Feb
PMID:Mouse models of triplet repeat diseases. 1644 16

Excessive body iron or iron overload occurs under conditions such as primary (hereditary) hemochromatosis and secondary iron overload (hemosiderosis), which are reaching epidemic levels worldwide. Primary hemochromatosis is the most common genetic disorder with an allele frequency greater than 10% in individuals of European ancestry, while hemosiderosis is less common but associated with a much higher morbidity and mortality. Iron overload leads to iron deposition in many tissues especially the liver, brain, heart and endocrine tissues. Elevated cardiac iron leads to diastolic dysfunction, arrhythmias and dilated cardiomyopathy, and is the primary determinant of survival in patients with secondary iron overload as well as a leading cause of morbidity and mortality in primary hemochromatosis patients. In addition, iron-induced cardiac injury plays a role in acute iron toxicosis (iron poisoning), myocardial ischemia-reperfusion injury, Friedreich ataxia and neurodegenerative diseases. Patients with iron overload also routinely suffer from a range of endocrinopathies, including diabetes mellitus and anterior pituitary dysfunction. Despite clear connections between elevated iron and clinical disease, iron transport remains poorly understood. While low-capacity divalent metal and transferrin-bound transporters are critical under normal physiological conditions, L-type Ca2+ channels (LTCC) are high-capacity pathways of ferrous iron (Fe2+) uptake into cardiomyocytes especially under iron overload conditions. Fe2+ uptake through L-type Ca2+ channels may also be crucial in other excitable cells such as pancreatic beta cells, anterior pituitary cells and neurons. Consequently, LTCC blockers represent a potential new therapy to reduce the toxic effects of excess iron.
J Mol Med (Berl) 2006 May
PMID:Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. 1660 32

Myotonic dystrophy type 2 (DM2) is caused by the extreme expansion of the repeating tetranucleotide CCTG*CAGG sequence from <30 repeats in normal individuals to approximately 11,000 for the full mutation in certain patients. This repeat is in intron 1 of the zinc finger protein 9 gene on chromosome 3q21. Since prior work demonstrated that CTG*CAG and GAA*TTC triplet repeats (responsible for DM1 and Friedreich's ataxia, respectively) can expand by genetic recombination, we investigated the capacity of the DM2 tetranucleotide repeats to also expand during this process. Both gene conversion and unequal crossing over are attractive mechanisms to effect these very large expansions. (CCTG*CAGG)n (where n=30, 75, 114 or 160) repeats showed high recombination crossover frequencies (up to 27-fold higher than the non-repeating control) in an intramolecular plasmid system in Escherichia coli. Furthermore, a distinct orientation effect was observed where orientation II (CAGG on the leading strand template) was more prone to recombine. Expansions of up to double the length of the tetranucleotide repeats were found. Also, the repeating tetranucleotide sequence was more prone to expansions (to give lengths longer than a single repeating tract) than deletions as observed for the CTG*CAG and GAA*TTC repeats. We determined that the DM2 tetranucleotide repeats showed a lower thermodynamic stability when compared to the DM1 trinucleotide repeats, which could make them better targets for DNA repair events, thus explaining their expansion-prone behavior. Genetic studies in SOS-repair mutants revealed high frequencies of recombination crossovers although the SOS-response itself was not induced. Thus, the genetic instabilities of the CCTG*CAGG repeats may be mediated by a recombination-repair mechanism that is influenced by DNA structure.
J Mol Biol 2006 Jun 30
PMID:DM2 CCTG*CAGG repeats are crossover hotspots that are more prone to expansions than the DM1 CTG*CAG repeats in Escherichia coli. 1675 77

The expanded GAA*TTC repeat sequence associated with Friedreich's ataxia (FRDA) adopts non-B DNA structures, (triplexes and sticky DNA). Sticky DNA is formed in plasmids by the association of two long GAA*TTC tracts at lengths that are found in the sequence of the frataxin gene in patients. Most FRDA patients have expanded GAA*TTC repeats (up to 1700 triplets), which inhibit the transcription of the gene, thus diminishing the synthesis of frataxin, a mitochondrial protein involved in iron-sulfur cluster biogenesis. Negative supercoiling and MgCl(2) (or MnCl(2)) are required to stabilize sticky DNA (a dumbbell-shaped structure) in plasmids with a pair of repeat tracts where n> or =60 in the direct repeat orientation in vitro. Since the triplet repeat sequences (TRS) were symmetrically positioned in the plasmids and because a number of unique restriction sites were present in the vector, studies were conducted to evaluate the influence of selectively linearizing one or the other supercoiled domains created by the DNA*DNA associated region, i.e. the stable complex at the pair of TRS's. The two domains behave independently, thus confirming the association of the two tracts and the dumbbell-shaped plasmid in our model for sticky DNA. Linking number investigations were performed on a family of plasmids harboring different lengths (30, 60, or 176 repeats), orientations and number of tracts (one or two) of a GAA*TTC repeat in Escherichia coli to evaluate the in vivo role, if any, of sticky DNA. Unexpectedly, this non-B DNA conformation elicited the formation of a TRS-length dependent change in the global topology of the plasmids, indicative of an apparent compression of the primary helices. Thus, linking number determinations confirm that sticky DNA has an important consequence in vivo.
J Mol Biol 2006 Jul 07
PMID:Sticky DNA: in vivo formation in E. coli and in vitro association of long GAA*TTC tracts to generate two independent supercoiled domains. 1676 89

Frataxin, a highly conserved protein found in prokaryotes and eukaryotes, is required for efficient regulation of cellular iron homeostasis. Humans with a frataxin deficiency have the cardio- and neurodegenerative disorder Friedreich's ataxia, commonly resulting from a GAA trinucleotide repeat expansion in the frataxin gene. While frataxin's specific function remains a point of controversy, the general consensus is that the protein assists in controlling cellular iron homeostasis by directly binding iron. This review focuses on the structural and biochemical aspects of iron binding by the frataxin orthologs and outlines molecular attributes that may help explain the protein's role in different cellular pathways.
Crit Rev Biochem Mol Biol
PMID:The structure and function of frataxin. 1691 56


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