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Titolo:
Friedreich's ataxia and frataxin: Molecular genetics, evolution and pathogenesis (Review)
Autore:
Palau, F;
Indirizzi:
CSIC, Lab Genet & Mol Med, Inst Biomed, Valencia 46010, Spain CSIC Valencia Spain 46010 & Mol Med, Inst Biomed, Valencia 46010, Spain Univ Valencia, Dept Genet, E-46003 Valencia, Spain Univ Valencia Valencia Spain E-46003 Dept Genet, E-46003 Valencia, Spain
Titolo Testata:
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
fascicolo: 6, volume: 7, anno: 2001,
pagine: 581 - 589
SICI:
1107-3756(200106)7:6<581:FAAFMG>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
GAA TRIPLET-REPEAT; TRINUCLEOTIDE REPEAT; CLINICAL-FEATURES; IRON ACCUMULATION; MISSENSE MUTATION; POINT MUTATIONS; IN-VIVO; DIAGNOSTIC-CRITERIA; PRENATAL-DIAGNOSIS; YEAST FRATAXIN;
Keywords:
Friedreich's ataxia; frataxin;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
78
Recensione:
Indirizzi per estratti:
Indirizzo: Palau, F CSIC, Lab Genet & Mol Med, Inst Biomed, C-Jaume Roig 11, Valencia46010, Spain CSIC C-Jaume Roig 11 Valencia Spain 46010 Valencia 46010, Spain
Citazione:
F. Palau, "Friedreich's ataxia and frataxin: Molecular genetics, evolution and pathogenesis (Review)", INT J MOL M, 7(6), 2001, pp. 581-589

Abstract

Friedreich's ataxia is an autosomal recessive neurodegenerative disorder involving both central and peripheral nervous system. Patients also show a systemic clinical picture presenting heart disease and diabetes mellitus or glucose intolerance. The disease is caused by mutations in the FRDA gene mapped on chromosome 9q13. The product of the gene is frataxin, an 18 kDa soluble mitochondrial protein with 210 amino acids. Crystal structure suggestsa new, not previously reported, protein fold. The most frequent mutation is the expansion of a GAA trinucleotide repeat located within the first intron of the gene, and represents 98% of the mutations. Point mutations are described in compound heterozygous subjects with one expanded allele. A two-step model of GAA normal alleles towards premutation alleles, which might generate further full expanded mutations in the population with Indo-Europeanancestry, has been postulated. Clinical phenotype is variable and an inverse correlation with the GAA expansion size has been observed. Analysis of the GAA tripler is a strong molecular tool for clinical diagnosis, genetic counselling and prenatal diagnosis. Friedreich's ataxia patho-genesis is notsolved yet. Substantial data from organism models, such the S. cerevisae yeast and more recently conditioned knock-outs in mouse, and studies in heart biopsies and fibroblast cultures from patients suggest an important role of mitochondrial iron in the development of the disease. Iron is accumulated in the mitochondrial matrix of both the yeast frataxin deficient mutant and the patient fibroblasts. It has been postulated that iron-induced oxygenradical affects the oxidative phosphorylation in frataxin deficiency states favouring the disease pathology. A second hypothesis postulate's a directrole of frataxin in the mitochondrial energy activation and oxidative phosphorylation. Iron chelator drugs and antioxidant drugs have been postulatedfor Friedreich's treatment. No results from clinical trials are available yet, but idebenone, a short-chain quinone, seems to reduce the size of hypertrophic cardiomyopathy and levels of oxidative stress molecules in patients.

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Documento generato il 21/01/20 alle ore 06:50:26