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's ataxia is due to loss of function mutations in the gene encoding frataxin (FRDA). Frataxin is a protein of unknown function. In situ hybridization analyses revealed that mouse frataxin expression correlates well with the main site of neurodegeneration, but the expression pattern is broader than expected from the pathology of the disease. Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate, including liver, kidney, brown fat and heart. We found that mouse and yeast frataxin homologues contain a potential mitochondrial targeting sequence in their N-terminal domains and that disruption of the yeast gene results in mitochondrial dysfunction. Finally, tagging experiments demonstrate that human frataxin co-localizes with a mitochondrial protein. Friedreich's ataxia is therefore a mitochondrial disease caused by a mutation in the nuclear genome.
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PMID:Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. 924 Dec 70

Friedreich's ataxia (FRDA) is an autosomal recessive degenerative disorder that primarily affects the nervous system and heart. Patients with FRDA have point mutations or trinucleotide repeat expansions in both alleles of FRDA, which encodes a protein termed frataxin. We show that the yeast frataxin homologue, which we have named YFH1, localizes to mitochondria and is required to maintain mitochondrial DNA. The YFH1-homologous domain of frataxin functions in yeast and a disease-associated missense mutation of this domain, or the corresponding domain in YFH1, reduces function. Our data suggest that mitochondrial dysfunction contributes to FRDA pathophysiology.
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PMID:Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. 924 Dec 71

The Friedreich ataxia (FA) mutation has recently been identified as an unstable trinucleotide GAA repeat present 7-22 times in the normal population but amplified as many as > 1,000 times in FA. Since it is an autosomal recessive disease, FA does not show typical features observed in other dynamic mutation disorders, such as genetic anticipation. We have analyzed the GAA repeat in 104 FA patients and 163 carrier relatives previously defined by linkage analysis. The GAA expansion was detected in all patients, most (94%) of them being homozygous for the mutation. We have demonstrated that clinical variability in FA is related to the size of the expanded alleles: milder forms of the disease-late-onset FA and FA with retained reflexes-are associated with shorter expansions, especially with the smaller of the two expanded alleles. Absence of cardiomyopathy is also associated with shorter alleles. Dynamics of the GAA repeat has been investigated in 212 parent-offspring pairs. Meiotic instability showed a sex bias: paternally transmitted alleles tend to decrease in a linear way that depends on the paternal expansion size, whereas maternal alleles can either increase or decrease. A different pattern of intergenerational variation was also observed, depending on the genetic status of the sib: patients had shorter expansions than were seen in heterozygous carriers. This finding has been interpreted as a postzygotic event. Finally, we have observed that the size of the expansion remains constant in the population through carriers.
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PMID:Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. 924 90

The most common mutation causing Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disease, is the hyperexpansion of a polymorphic GAA triplet repeat localized within an Alu sequence (GAA-Alu) in the first intron of the frataxin (X25) gene. GAA-Alu belongs to the AluSx subfamily and contains several polymorphisms in strong linkage disequilibrium either with a subgroup of normal alleles, or with hyperexpanded FRDA-associated alleles. GAA repeat sizes in 300 normal chromosomes (97 from carriers and 203 from controls) were distributed in two separate groups: 83% of them contained between six and 10 triplets (small normal alleles), while the remaining 17% had more than 12 triplets, up to 36 (large normal alleles). Sequence analysis showed that no normal, stable allele contained more than 27 uninterrupted GAA triplets. All longer normal alleles were interrupted by a hexanucleotide repeat (GAGGAA). An allele containing an uninterrupted run of 34 GAA triplets was stably transmitted in four instances, but in one case underwent hyperexpansion to 650 triplets. Overall, our results suggest that the FRDA-associated expanded GAA repeats originate from normal alleles by recurrent expansions of alleles at risk.
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PMID:The Friedreich ataxia GAA triplet repeat: premutation and normal alleles. 925 71

Friedreich's ataxia is caused by a triplet repeat expansion in intron 1, a noncoding region of the frataxin gene (X25). We have generated a chimeric gene composed of the frataxin gene fused with the green fluorescent protein (GFP) gene as a reporter. Transfection of the fusion construct into living COS cells revealed that the frataxin-GFP construct localizes to organelles that double-label with 8-(4'-chloromethyl) phenyl-2,3,5,6,11,12,14,15-octahydro-1H,4H,10H-13H-diquinolizin o-8H-xanthylium chloride (CMXRos), a novel mitochondrial dye. Thus, frataxin appears to be a nuclear-encoded mitochondrial protein.
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PMID:Frataxin gene of Friedreich's ataxia is targeted to mitochondria. 926 41

Most patients with Friedreich's ataxia (FRDA) carry expanded GAA repeats in both homologues of the frataxin gene on chromosome 9. We determined the size of the GAA repeats in autopsied samples from the CNS of six FRDA patients. We observed heterogeneity of repeat sizes in different CNS regions, indicative of extensive mitotic instability. Samples from the same CNS subdivision (e.g., cortex, thalamus) contained a similar mixture of alleles, suggesting that the pattern of repeat size mosaicism reflects the developmental history of each sample. Regional differences in repeat size could not account for the characteristic distribution of pathology in FRDA, which appears instead to be related to the pattern of frataxin expression.
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PMID:Somatic mosaicism for Friedreich's ataxia GAA triplet repeat expansions in the central nervous system. 927 Jun 8

Phenotypic variants in Friedreich's ataxia include late onset, preservation of the lower limbs tendon reflexes, and slow progression. We describe clinical and electrophysiological features from three families with Friedreichlike phenotypes. Friedreich's ataxia diagnosis was confirmed by finding two allelic expansions of the GAA trinucleotide repeat at the X25 gene. In family 1 both patients had a late-onset phenotype with preservation of knee and ankle jerks, lack of cardiomyopathy, and preserved H reflex. One of them did not have electrophysiologic evidence of sensory axonal neuropathy. Patients from family 2 showed variability in the age of onset, and 2 out of 3 affected children had hyperactive lower limbs reflexes with preserved H reflex. Disease progression in a patient from family 3 was very slow after onset at the age of 21. The finding of two expanded alleles in these families confirms the wide variability of the clinical spectrum of Friedreich's ataxia.
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PMID:GAA trinucleotide repeat expansion in variant Friedreich's ataxia families. 927 Jun 67

Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.
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PMID:Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. 930 53

Friedreich ataxia (FRDA) is a common autosomal recessive degenerative disease (1/50,000 live births) characterized by a progressive-gait and limb ataxia with lack of tendon reflexes in the legs, dysarthria and pyramidal weakness of the inferior limbs. Hypertrophic cardiomyopathy is observed in most FRDA patients. The gene associated with the disease has been mapped to chromosome 9q13 (ref. 3) and encodes a 210-amino-acid protein, frataxin. FRDA is caused primarily by a GAA repeat expansion within the first intron of the frataxin gene, which accounts for 98% of mutant alleles. The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA patients and in mitochondria of yeast strains carrying a deleted frataxin gene counterpart (YFH1), suggesting that frataxin plays a major role in regulating mitochondrial iron transport. Here, we report a deficient activity of the iron-sulphur (Fe-S) cluster-containing subunits of mitochondrial respiratory complexes I, II and III in the endomyocardial biopsy of two unrelated FRDA patients. Aconitase, an iron-sulphur protein involved in iron homeostasis, was found to be deficient as well. Moreover, disruption of the YFH1 gene resulted in multiple Fe-S-dependent enzyme deficiencies in yeast. The deficiency of Fe-S-dependent enzyme activities in both FRDA patients and yeast should be related to mitochondrial iron accumulation, especially as Fe-S proteins are remarkably sensitive to free radicals. Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA, which should therefore be regarded as a mitochondrial disorder.
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PMID:Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. 932 46

We collected 7 Friedreich ataxia (FRDA) pedigrees from France. All cases but one family were homozygous for an unstable GAA trinucleotide expansion in the first intron of the frataxin gene. In this peculiar pedigree absence of the GAA expansion supports the notion of possible genetic heterogeneity of FRDA.
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PMID:Trinucleotide GAA repeat expansions in seven French Friedreich ataxia families. 932 60


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