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)

Friedreich ataxia is commonly caused by large expansions of a GAA triplet-repeat (GAA-TR) sequence in the first intron of the FRDA gene. We used small-pool PCR to analyze somatic variability among 7190 individual FRDA molecules from peripheral blood DNA of subjects carrying 12 different expanded alleles, ranging in size from 241 to 1105 triplets. Expanded alleles showed a length-dependent increase in somatic variability, with mutation loads ranging from 47% to 78%. We noted a strong contraction bias among long alleles (>500 triplets), which showed a 4-fold higher frequency of large contractions versus expansions. Some contractions were very large; of all somatic mutations scored, approximately 5% involved contractions of >50% of the original allele length, and 0.29% involved complete reversion to the normal/premutation length (< or =60 triplets). These observations contrast sharply with the strong expansion bias seen in expanded CTG triplet repeats in myotonic dystrophy. No somatic variability was detected in >6000 individual FRDA molecules analyzed from 15 normal alleles (8-25 triplets). A premutation allele with 44 uninterrupted GAA repeats was found to be unstable, ranging in size from 6 to 113 triplets, thus establishing the threshold for somatic instability between 26 and 44 GAA triplets. Analysis of an additional 7850 FRDA molecules from serially passaged lymphoblastoid cell lines carrying nine expanded alleles (132-933 triplets) showed very low mutation loads, ranging from 0% to 6.2%. Our data indicate that expanded GAA-TR alleles in Friedreich ataxia are highly mutable and have a natural tendency to contract in vivo, and that these properties depend on multiple factors, including DNA sequence, triplet-repeat length and unknown cell-type-specific factors.
Hum Mol Genet 2002 Sep 01
PMID:The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo, with a significant predilection for large contractions. 1218 70

Friedreich's ataxia is caused by a deficit in frataxin, a small mitochondrial protein of unknown function that has been conserved during evolution. Previous studies have pointed out a role for frataxin in mitochondrial iron-sulfur (Fe-S) metabolism. Here, we have analyzed the incorporation of Fe-S clusters into yeast ferredoxin imported into isolated energized mitochondria from cells grown in the presence of glycerol, an obligatory respiratory carbon source. Similar amounts of apo-ferredoxin precursor were imported into mitochondria and processed in wild-type and yfh1-deleted (delta YF111) strains. However, the incorporation of Fe-S clusters into apo-ferredoxin was significantly reduced in delta YFH1 mitochondria. The newly assembled ferredoxin was stable, excluding the possibility that the decreased incorporation was a result of increased oxidative damage. When delta YFH1 cells were grown in raffinose medium, the formation of holo-ferredoxin was low, as a consequence of the decrease in ferredoxin precursor import into mitochondria. However, the decrease in the conversion rate of apo- into holo-ferredoxin was in the same range as for glycerol-grown cells, indicating that the extent of the defect in Fe-S protein assembly is similar under different physiological conditions. These data show that frataxin is not essential for Fe-S protein assembly, but improves the efficiency of the process. The large variations observed in the activity of Fe-S cluster proteins under different physiological conditions result from secondary defects in the physiology of delta YFH1 cells.
Hum Mol Genet 2002 Oct 01
PMID:A non-essential function for yeast frataxin in iron-sulfur cluster assembly. 1235 89

The severe reduction in mRNA and protein levels of the mitochondrial protein frataxin, encoded by the X25 gene, causes Friedreich ataxia (FRDA), the most common form of recessive hereditary ataxia. Increasing evidence underlines the pathogenetic role of oxidative stress in this disease. We generated an in vitro cellular model of regulated human frataxin overexpression. We identified, by differential display technique, the mitogen activated protein kinase kinase 4 mRNA down regulation in frataxin overexpressing cells. We studied the stress kinases pathway in this cellular model and in fibroblasts from FRDA patients. Frataxin overexpression reduced c-Jun N-terminal kinase phosphorylation. Furthermore, exposure of FRDA fibroblasts to several forms of environmental stress caused an up regulation of phospho-JNK and phospho-c-Jun. To understand if this susceptibility results in cell death, we have investigated the involvement of caspases. A significantly higher activation of caspase-9 was observed in FRDA versus control fibroblasts after serum-withdrawal. Our findings suggest the presence, in FRDA patient cells, of a 'hyperactive' stress signaling pathway. The role of frataxin in FRDA pathogenesis could be explained, at least in part, by this hyperactivity.
Hum Mol Genet 2002 Nov 01
PMID:Up-regulation of c-Jun N-terminal kinase pathway in Friedreich's ataxia cells. 1239 10

Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi-systemic disease with loss of sensory neurons and life-threatening hypertrophic cardiomyopathy as its most severe manifestations. Reduced levels of the mitochondrial protein frataxin lead to cell-damaging oxidative stress and consequently FRDA is considered as a model for more common neurodegenerative disorders in which reactive radicals and oxidative stress are involved. We have developed a cellular assay system that discriminates between fibroblasts from FRDA patients and unaffected donors on the basis of their sensitivity to pharmacological inhibition of de novo synthesis of glutathione. With this assay we observed that supplementation with selenium effectively improved the viability of FRDA fibroblasts, indicating that basal selenium concentrations are not sufficient to allow an adequate increase in the activity of certain detoxification enzymes (such as GPX). Furthermore, we characterized potential drug candidates and found that idebenone, a mitochondrially localized antioxidant that ameliorates cardiomyopathy in FRDA patients, as well as other lipophilic antioxidants protected FRDA cells from cell death. Our results also demonstrate for the first time that small-molecule GPX mimetics have potential as a novel treatment strategy for Friedreich Ataxia and presumably also for other neurodegenerative diseases with mitochondrial impairment.
Hum Mol Genet 2002 Nov 15
PMID:A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy. 1241 27

Friedreich ataxia is an autosomal recessive disease causing degeneration in the central and peripheral nervous system, cardiomyopathy, skeletal abnormalities and increased risk of diabetes. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded mitochondrial protein. The genetic mutation found in 98% of Friedreich ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the gene. The expanded GAA repeat, by adopting an abnormal triple helical structure, impairs frataxin transcription. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Yeast cells deficient in the frataxin homologue (Deltayfh1) become unable to carry out oxidative phosphorylation, lose mitochondrial DNA, accumulate iron in mitochondria, show unregulated high expression of high affinity iron uptake, and have an increased sensitivity to oxidative stress. Loss of respiratory competence in Deltayfh1 is iron-dependent. Additional properties of these cells include a deficiency of iron-sulfur cluster containing proteins (ISPs) and impaired iron efflux out of mitochondria. Evidence of oxidative stress, mitochondrial dysfunction, deficiency of multiple ISPs and iron deposits are also found in the human disease and in mouse models. The primary function of frataxin is still unknown, however much recent evidence suggests that it enhances iron-sulfur cluster synthesis and protects iron from free radical-generating reactions. The search for frataxin function stimulated more investigations on the role of mitochondria in cellular iron homeostasis. Their results suggest that these organelles may play a central role in controlling iron homeostasis, which is not surprising considering that they are the major cellular site where this metal is utilized. I propose a model, valid in yeast as well as in higher eukaryotes, in which iron transport into mitochondria is directly coupled to its uptake at the cell membrane and iron transport out of mitochondria depends on adequate iron-sulfur cluster synthesis. Regulatory mechanisms in the cytosol would then sense a post-mitochondrial iron pool. Much circumstantial evidence from genetically manipulated yeast and from human diseases supports this model.
Blood Cells Mol Dis
PMID:Iron metabolism and mitochondrial abnormalities in Friedreich ataxia. 1254 48

Inherited deficiency of the mitochondrial protein frataxin causes neural and cardiac cell degeneration, and Friedreich's ataxia. Five hypotheses for frataxin's mitochondrial function have been generated, largely from work in non-human cells: iron transporter, iron-sulfur cluster assembler, iron-storage protein, antioxidant and stimulator of oxidative phosphorylation. We analyzed gene expression in three human cell types using microarrays, and identified just 48 transcripts whose expression was significantly frataxin-dependent in at least two cell types. Significant decreases in seven transcripts occurred in the sulfur amino acid (SAA) biosynthetic pathway and the iron-sulfur cluster (ISC) biosynthetic pathway to which it is connected. By contrast, we did not observe a single frataxin-dependent transcript that fits with the other four current hypotheses. Quantitative reverse-transcriptase PCR analysis of ISC-S and rhodanese transcripts confirmed that the expression of these genes involved in ISC metabolism was lower in mutants. Amino acid analysis confirmed the defect in SAA metabolism: homocystine, cysteine, cystathionine and serine were significantly decreased in frataxin-deficient cell extracts and mitochondria. An ISC defect was further confirmed by observing decreases in succinate dehydrogenase and aconitase activities, whose activities require ISCs. The ISC-U scaffold protein was specifically decreased in frataxin-deficient cells, suggesting a role for frataxin in its expression or maintenance, and sodium sulfide partially rescued the oxidant-sensitivity of the FRDA cells. Also, multiple transcripts involved in the Fas/TNF/INF apoptosis pathway were up-regulated in frataxin-deficient cells, consistent with a multi-step mechanism of Friedreich's ataxia pathophysiology, and suggesting alternative possibilities for therapeutic intervention.
Hum Mol Genet 2003 Jul 15
PMID:Decreased expression of genes involved in sulfur amino acid metabolism in frataxin-deficient cells. 1283 93

Frataxin protein controls iron availability in mitochondria and reduced levels lead to the human disease, Friedreich's ataxia (FRDA). The molecular aspects of disease progression are not well understood. We developed a highly regulatable promoter system for expressing frataxin in yeast to address the consequences of chronically reduced amounts of this protein. Shutting off the promoter resulted in changes normally associated with loss of frataxin including iron accumulation within the mitochondria and the induction of mitochondrial petite mutants. While there was considerable oxidative damage to mitochondrial proteins, the petites were likely due to accumulation of mitochondrial DNA lesions and subsequent DNA loss. Chronically reduced frataxin levels resulted in similar response patterns. Furthermore, nuclear DNA damage was detected in a rad52 mutant, deficient in double-strand break repair. We conclude that reduced frataxin levels, which is more representative of the disease state, results in considerable oxidative damage in both mitochondrial and nuclear DNA.
Hum Mol Genet 2003 Dec 15
PMID:Reduction in frataxin causes progressive accumulation of mitochondrial damage. 1457 Jul 13

Hypertrophic cardiomyopathy is a Mendelian disease characterized by cardiac hypertrophy. It has a prevalence of 1:500 individuals and is the most common cause of sudden death in the young. Other complications include heart failure and the need for heart transplantation. Hypertrophic cardiomyopathy is due to sarcomeric gene mutations, however, phenocopies with myocardial hypertrophy can be due to triplet-repeat syndromes (Friedreich ataxia and myotonic dystrophy), mitochondrial and metabolic diseases. In a peculiar form associated with Wolf-Parkinson-White syndrome, the disease is caused by mutations in the gamma2 regulatory subunit of the AMP-activated protein kinase gene, leading to a glycogen storage cardiomyopathy. In spite of the growing knowledge about the molecular basis of hypertrophic cardiomyopathy, very little is still known about the genotype-phenotype correlations and their clinical implications. In this review, the clinical and molecular genetics of hypertrophic cardiomyopathy are described.
Expert Rev Mol Diagn 2004 Jan
PMID:Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing. 1471 53

Friedreich's ataxia (GAA)n repeats of various lengths were cloned into a Saccharymyces cerevisiae plasmid, and their effects on DNA replication were analyzed using two-dimensional electrophoresis of replication intermediates. We found that premutation- and disease-size repeats stalled the replication fork progression in vivo, while normal-size repeats did not affect replication. Remarkably, the observed threshold repeat length for replication stalling in yeast (approximately 40 repeats) closely matched the threshold length for repeat expansion in humans. Further, replication stalling was strikingly orientation dependent, being pronounced only when the repeat's homopurine strand served as the lagging strand template. Finally, it appeared that length polymorphism of the (GAA)n. (TTC)n repeat in both expansions and contractions drastically increases in the repeat's orientation that is responsible for the replication stalling. These data represent the first direct proof of the effects of (GAA)n repeats on DNA replication in vivo. We believe that repeat-caused replication attenuation in vivo is due to triplex formation. The apparent link between the replication stalling and length polymorphism of the repeat points to a new model for the repeat expansion.
Mol Cell Biol 2004 Mar
PMID:Replication stalling at Friedreich's ataxia (GAA)n repeats in vivo. 1499 68

Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associated with cardiomyopathy, is caused by severely reduced frataxin, a mitochondrial protein involved in Fe-S cluster assembly. We have recently generated mouse models that reproduce important progressive pathological and biochemical features of the human disease. Our frataxin-deficient mouse models initially demonstrate time-dependent intramitochondrial iron accumulation, which occurs after onset of the pathology and after inactivation of the Fe-S dependent enzymes. Here, we report a more detailed pathophysiological characterization of our mouse model with isolated cardiac disease by echocardiographic, biochemical and histological studies and its use for placebo-controlled therapeutic trial with Idebenone. The Fe-S enzyme deficiency occurs at 4 weeks of age, prior to cardiac dilatation and concomitant development of left ventricular hypertrophy, while the mitochondrial iron accumulation occurs at a terminal stage. From 7 weeks onward, Fe-S enzyme activities are strongly decreased and are associated with lower levels of oxidative stress markers, as a consequence of reduced respiratory chain activity. Furthermore, we demonstrate that the antioxidant Idebenone delays the cardiac disease onset, progression and death of frataxin deficient animals by 1 week, but does not correct the Fe-S enzyme deficiency. Our results support the view that frataxin is a necessary, albeit non-essential, component of the Fe-S cluster biogenesis, and indicate that Idebenone acts downstream of the primary Fe-S enzyme deficit. Furthermore, our results demonstrate that Idebenone is cardioprotective even in the context of a complete lack of frataxin, which further supports its utilization for the treatment of FRDA.
Hum Mol Genet 2004 May 15
PMID:Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia. 1502 70


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