Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friedreich ataxia is a severe neurodegenerative autosomal recessive disorder of unknown biochemical defect. The Friedreich ataxia locus (FRDA) is tightly linked to the centromeric side of the D9S5 locus. We have used 'exon-trapping' to identify two new genes, approximately 100 and 200 kb centromeric to D9S5, respectively. One gene appears ubiquitously expressed while the other is prominently expressed in muscle. The ubiquitous transcript codes for a protein containing a 20 aa repeat reminiscent of simple repeats found in several ribonucleoproteins. Using the single-strand conformation polymorphism (SSCP) procedure, we searched for mutations in affected patients in the coding sequence of the two genes, as well as in a gene that we had previously identified in the same region. Eight polymorphic DNA changes but no causative mutations were found, suggesting that the genes are not candidates for Friedreich ataxia. The discovery of a simple sequence repeat polymorphism in the most centromeric gene allowed the localization within that gene of the breakpoint of a previously described recombination in a Friedreich ataxia family, therefore excluding the two distal genes from the FRDA region. The lack of causative mutations in the three genes and the position of the recombination further delineate the FRDA locus to a 300 kb interval.
Hum Mol Genet 1994 Jun
PMID:The Friedreich ataxia region: characterization of two novel genes and reduction of the critical region to 300 kb. 795 Dec 35

Using a modified Repeat Expansion Detection (RED) assay, that was optimized for individual oligonucleotides, unrelated individuals were systematically screened for maximal repeat sizes of each of the ten possible trinucleotide repeats. Cloned trinucleotide repeats were generated and used as standards for the detectability of single copy trinucleotide repeat fragments. When the size distributions of trinucleotide repeats were compared to previously reported data, significant differences were found for the CTT repeat, which corresponds to the expanded GAA repeat in Friedreich ataxia, as well as for ATT, CCT and GTT repeats. Since 30-35% of normal individuals have CTG/CAG trinucleotide repeat sizes of 180 bp or more, we investigated the question whether small-scale CTG/CAG repeat expansions are detectable on a population basis by using the RED technique. We blindly screened 20 HD probands with CAG expansions of the HD gene, ranging in size between 120 and 174 bp, and found that a shift to larger CAG size ranges is clearly detectable when comparing the distribution of maximal repeat sizes in the disease group to a control group. Our study, therefore, demonstrates that the application of the RED assay to a population of probands and a population of controls allows the detection of small-scale CTG/CAG repeat expansions in the size range of the expanded HD gene and present in a single allele. We also provide standards and control data for the detection of other trinucleotide repeat expansions.
Hum Mol Genet 1997 Jan
PMID:Trinucleotide repeats in the human genome: size distributions for all possible triplets and detection of expanded disease alleles in a group of Huntington disease individuals by the repeat expansion detection method. 900 73

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.
Hum Mol Genet 1997 Aug
PMID:The Friedreich ataxia GAA triplet repeat: premutation and normal alleles. 925 71

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.
Hum Mol Genet 1997 Oct
PMID:Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. 930 53

Frataxin is a mitochondrial protein deficient in Friedreich ataxia (FRDA) and which is associated with abnormal intramitochondrial iron handling. We identified the mitochondrial processing peptidase beta (MPPbeta) as a frataxin protein partner using the yeast two-hybrid assay. In in vitro assays, MPPbeta binds frataxin which is cleaved by the reconstituted MPP heterodimer. MPP cleavage of frataxin results in an intermediate form (amino acids 41-210) that is processed further to the mature form. In vitro and in vivo experiments suggest that two C-terminal missense mutations found in FRDA patients modulate interaction with MPPbeta, resulting in a slower maturation process at the normal cleavage site. The slower processing rate of frataxin carrying such missense mutations may therefore contribute to frataxin deficiency, in addition to an impairment of its function.
Hum Mol Genet 1998 Sep
PMID:Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase. 970 Feb 4

Friedreich's ataxia is the first known autosomal recessive disease caused by an unstable trinucleotide expansion mutation. The most frequent mutation is expansion of a GAA repeat in the first intron of gene X25. We studied transmission of the expanded GAA repeat in 37 Friedreich's ataxia pedigrees and analysed blood and sperm alleles in eight patients. We showed intergenerational instability in 84% of the alleles with an overall excess of contractions. Both contractions and expansions of the GAA repeat occurred in maternal transmission with a stronger tendency to expand for smaller repeats and to contract for longer repeats. Paternally transmitted alleles contracted only. Parental age and the intergenerational change in expansion size were directly correlated in maternal transmission and inversely in paternal transmission. The size of the GAA expansion was slightly lower in patients than heterozygous carriers. Sperm analysis confirmed the tendency to contract of paternal alleles, which was more marked with ageing. The degree of contraction of the GAA repeat in sperm was much higher than that found in intergenerational transmission and was directly related to the repeat size. A blood expanded allele reverted to normal size in the sperm of one patient. This study suggests the existence of different mutational mechanisms in Friedreich's ataxia alleles, which occur both pre- and post-zygotically.
Hum Mol Genet 1998 Nov
PMID:Parental gender, age at birth and expansion length influence GAA repeat intergenerational instability in the X25 gene: pedigree studies and analysis of sperm from patients with Friedreich's ataxia. 981 33

Expansions of the triplet repeat, GAA/TTC, inside the first intron of the frataxin gene causes Friedreich's ataxia (FRDA). It was of interest to us to examine whether the FRDA repeat forms an unusual DNA structure, since formation of such structure during replication may cause its expansion. Here, we show that the FRDA repeat forms a triplex in which the TTC strand folds on either side of the same GAA strand. We have determined the high-resolution NMR structures of two intramolecularly folded FRDA triplexes, (GAA)2T4(TTC)2T4(CTT)2 and (GAA)2T4(TTC)2T2CT2(CTT)2 with T.A.T and C+.G.C triads. T4 represents a synthetic loop sequence, whereas T2CT2 is the natural loop-folding sequence of the TTC strand. We have also made use of site-specific 15N-labeling of the cytosine residues to investigate their protonation status and their interaction with other protons. We show that the cytosine residues of the Hoogsteen C+.G pairs in this triplex are protonated close to physiological pH. Therefore, it appears that the triplex formation offers a plausible explanation for the expansion of the GAA/TTC repeats in FRDA.
J Mol Biol 1999 Feb 05
PMID:The high-resolution structure of the triplex formed by the GAA/TTC triplet repeat associated with Friedreich's ataxia. 992 83

Expansions of an intronic GAA repeat reduce the expression of frataxin and cause Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease. Frataxin is a mitochondrial protein, and disruption of a frataxin homolog in yeast results in increased sensitivity to oxidant stress, increased mitochondrial iron and respiration deficiency. These previous data support the hypothesis that FRDA is a disease of mitochondrial oxidative stress, a hypothesis we have tested in cultured cells from FRDA patients. FRDA fibroblasts were hypersensitive to iron stress and significantly more sensitive to hydrogen peroxide than controls. The iron chelator deferoxamine rescued FRDA fibroblasts more than controls from oxidant-induced death, consistent with a role for iron in the differential kinetics of death; however, mean mitochondrial iron content in FRDA fibroblasts was increased by only 40%. Treatment of cells with the intracellular Ca2+chelator BAPTA-AM rescued both FRDA fibroblasts and controls from oxidant-induced death. Treatment with apoptosis inhibitors rescued FRDA but not control fibroblasts from oxidant stress, and staurosporine-induced caspase 3 activity was higher in FRDA fibroblasts, consistent with the possibility that an apoptotic step upstream of caspase 3 is activated in FRDA fibroblasts. These results demonstrate that FRDA fibroblasts are sensitive to oxidant stress, and may be a useful model in which to elucidate the FRDA mechanism and therapeutic strategies.
Hum Mol Genet 1999 Mar
PMID:The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. 994 1

Background: Friedreich ataxia, an autosomal recessive neurodegenerative disease, is one of the recently identified trinucleotide repeat disorders. Approximately 94% of affected individuals are homozygous for an intronic GAA repeat within the frataxin gene. The identification of this trinucleotide expansion as the causative mutation in the majority of affected individuals has resulted in the availability of molecular testing for Friedreich ataxia in the clinical molecular diagnostics laboratory. Methods and Results: A Friedreich ataxia protocol has been implemented using two long-range polymerase chain reaction-based assays primed with the GAA-F/GAA-R and Bam/2500F primer sets [1]. The amplified products are analyzed on precast minigels and visualized by Sybr Green staining. The GAA primer set, which produces a normal product of approximately 500 bp and an expanded product of greater than 800 bp, is used to approximate the size range of expanded repeats. Because the GAA primer set occasionally demonstrates preferential amplification of the normal allele in heterozygotes, the Bam/2500F primer set is used to verify results. Conclusions: This protocol has been used to analyze 42 specimens from patients about whom we had detailed clinical information. Concordant results obtained from the GAA and Bam/2500F primer sets, as well as correlations between clinical information and molecular results, indicate that, for the majority of patient specimens, this protocol allows rapid analysis and sizing of GAA repeats in normal and expanded alleles.
Mol Diagn 1998 Mar
PMID:Long Range Polymerase Chain Reaction-Based Diagnosis of Friedreich Ataxia in the Clinical Molecular Diagnostics Laboratory. 1009 52

A novel DNA structure, sticky DNA, is described for lengths of (GAA.TTC)n found in intron 1 of the frataxin gene of Friedreich's ataxia patients. Sticky DNA is formed by the association of two purine.purine.pyrimidine (R.R.Y) triplexes in negatively supercoiled plasmids at neutral pH. An excellent correlation was found between the lengths of (GAA.TTC) (> 59 repeats): first, in FRDA patients, second, required to inhibit transcription in vivo and in vitro, and third, required to adopt the sticky conformation. Fourth, (GAAGGA.TCCTTC)65, also found in intron 1, does not form sticky DNA, inhibit transcription, or associate with the disease. Hence, R.R.Y triplexes and/or sticky DNA may be involved in the etiology of FRDA.
Mol Cell 1999 Apr
PMID:Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich's ataxia. 1023 Mar 99


1 2 3 4 5 6 7 8 9 10 Next >>