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

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

Friedreich's ataxia (FRDA) is a neurodegenerative disease typically caused by a deficiency of frataxin, a mitochondrial protein of unknown function. In Saccharomyces cerevisiae, lack of the yeast frataxin homolog ( YFH1 gene, Yfh1p polypeptide) results in mitochondrial iron accumulation, suggesting that frataxin is required for mitochondrial iron homeostasis and that FRDA results from oxidative damage secondary to mitochondrial iron overload. This hypothesis implies that the effects of frataxin deficiency could be influenced by other proteins involved in mitochondrial iron usage. We show that Yfh1p interacts functionally with yeast mitochondrial intermediate peptidase ( OCT1 gene, YMIP polypeptide), a metalloprotease required for maturation of ferrochelatase and other iron-utilizing proteins. YMIP is activated by ferrous iron in vitro and loss of YMIP activity leads to mitochondrial iron depletion, suggesting that YMIP is part of a feedback loop in which iron stimulates maturation of YMIP substrates and this in turn promotes mitochondrial iron uptake. Accordingly, YMIP is active and promotes mitochondrial iron accumulation in a mutant lacking Yfh1p ( yfh1 [Delta]), while genetic inactivation of YMIP in this mutant ( yfh1 [Delta] oct1 [Delta]) leads to a 2-fold reduction in mitochondrial iron levels. Moreover, overexpression of Yfh1p restores mitochondrial iron homeostasis and YMIP activity in a conditional oct1 ts mutant, but does not affect iron levels in a mutant completely lacking YMIP ( oct1 [Delta]). Thus, we propose that Yfh1p maintains mitochondrial iron homeostasis both directly, by promoting iron export, and indirectly, by regulating iron levels and therefore YMIP activity, which promotes mitochondrial iron uptake. This suggests that human MIP may contribute to the functional effects of frataxin deficiency and the clinical manifestations of FRDA.
Hum Mol Genet 1999 Jun
PMID:Mitochondrial intermediate peptidase and the yeast frataxin homolog together maintain mitochondrial iron homeostasis in Saccharomyces cerevisiae. 1033 43

Frataxin is a nuclear-encoded mitochondrial protein which is deficient in Friedreich's ataxia, a hereditary neurodegenerative disease. Yeast mutants lacking the yeast frataxin homologue (Yfh1p) show iron accumulation in mitochondria and increased sensitivity to oxidative stress, suggesting that frataxin plays a critical role in mitochondrial iron homeostasis and free radical toxicity. Both Yfh1p and frataxin are synthesized as larger precursor molecules that, upon import into mitochondria, are subject to two proteolytic cleavages, yielding an intermediate and a mature size form. A recent study found that recombinant rat mitochondrial processing peptidase (MPP) cleaves the mouse frataxin precursor to the intermediate but not the mature form (Koutnikova, H., Campuzano, V., and Koenig, M. (1998) Hum. Mol. Gen. 7, 1485-1489), suggesting that a different peptidase might be required for production of mature size frataxin. However, in the present study we show that MPP is solely responsible for maturation of yeast and human frataxin. MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to mature size protein. In this way, MPP could influence frataxin function and indirectly affect mitochondrial iron homeostasis.
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PMID:Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase. 1042 60

Friedreich's ataxia is a neurodegenerative disease caused by mutations in the nuclear gene encoding frataxin (FRDA). FRDA is synthesized with an N-terminal signal sequence, which is removed after import into mitochondria. We have shown that FRDA was imported efficiently into isolated mammalian or yeast mitochondria. In both cases, the processing cleavage that removed the N-terminal signal sequence occurred in a single step on import, generating mature products of identical mobility. The processing cleavage could be reconstituted by incubating the FRDA preprotein with rat or yeast matrix processing peptidase (MPP) expressed in Escherichia coli. We used these assays to evaluate the import and processing of an altered form of FRDA containing the disease-causing I154F mutation. No effects on import or maturation of this mutated FRDA were observed. Likewise, no effects were observed on import and maturation of the yeast frataxin homolog (Yfh1p) carrying a homologous I130F mutation. These results argue against the possibility that the I154F mutation interferes with FRDA function via effects on maturation. Other mutations can be screened for effects on FRDA biogenesis as described here, by evaluating import into isolated mitochondria and by testing maturation with purified MPP.
Hum Mol Genet 1999 Nov
PMID:Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase. 1054 6

The vast majority of Friedreich ataxia patients are homozygous for large GAA triplet repeat expansions in intron 1 of the X25 gene. Instability of the expanded GAA repeat was examined in 23 chromosomes bearing 97-1250 triplets in lymphoblastoid cell lines passaged 20-39 times. Southern analyses revealed 18 events of significant changes in length ranging from 69 to 633 triplets, wherein the de novo allele gradually replaced the original over 1-6 passages. Contractions and expansions occurred with equal frequency and magnitude. This behavior is unique in comparison with other large, non-coding triplet repeat expansions [(CGG)(n)and (CTG)(n)] which remain relatively stable under similar conditions. We also report a rare patient who, having inherited two expanded alleles, showed evidence of contracted GAA repeats ranging from nine to 29 triplets in DNA from two independent peripheral blood samples. The GAA triplet repeat is known to adopt a triplex structure, and triplexes in transcribed templates cause enhanced mutagenesis. The poly(A) tract and a 135 bp sequence, both situated immediately upstream of the GAA triplet repeat, were therefore examined for somatic mutations. The poly(A) tract showed enhanced instability when in cis with the GAA expansion. The 135 bp upstream sequence was found to harbor a 3-fold excess of point mutations in DNA derived from individuals homozygous for the GAA triplet repeat expansion compared with normal controls. These data are likely to have important mechanistic and clinical implications.
Hum Mol Genet 1999 Dec
PMID:Somatic sequence variation at the Friedreich ataxia locus includes complete contraction of the expanded GAA triplet repeat, significant length variation in serially passaged lymphoblasts and enhanced mutagenesis in the flanking sequence. 1055 90

We have isolated a Saccharomyces cerevisiae mutant that shows an increased tendency to form cytoplasmic petites (respiration-deficient rho- or rho0 mutants) in response to treatment of cells growing on a solid medium with the DNA-damaging agent methyl methane-sulfonate or ultraviolet light. The mutation in this strain, atm1-1, was found to cause a single amino acid substitution in ATM1, a nuclear gene that encodes the mitochondrial ATP-binding cassette (ABC) transporter. When the mutant cells were grown in liquid glucose medium, they accumulated free iron within the mitochondria and at the same time gave rise to spontaneous cytoplasmic petite mutants, as seen previously in cells carrying a mutation in a gene homologous to the human gene responsible for Friedreich's ataxia. Analysis of the effects of free iron and malonic acid (an inhibitor of oxidative respiration in mitochondria) on the incidence of petites among the mutant cells indicated that spontaneous induction of petites was a consequence of oxidative stress rather than a direct effect of either a defect in the ATM1 gene or the accumulation of free iron. We observed an increase in the incidence of strand breaks in the mitochondrial DNA of the atm1-1 mutant cells. Furthermore, we found that rates of induction of petites and accumulation of strand breaks in mitochondrial DNA were enhanced in the atm1-1 mutant by the introduction of another mutation, mhr1-1, which results in a deficiency in mitochondrial DNA repair. These observations indicate that spontaneous induction of petites in the atm1-1 mutant is a consequence of oxidative damage to mitochondrial DNA mediated by enhanced accumulation of mitochondrial iron.
Mol Gen Genet 1999 Oct
PMID:A mutation in a mitochondrial ABC transporter results in mitochondrial dysfunction through oxidative damage of mitochondrial DNA. 1058 29


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