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Friedreich's ataxia
and frataxin:
Molecular genetics, evolution and pathogenesis.
Palau F.
Instituto de Biomedicina de Valencia,
CSIC, 46010 Valencia, Spain.
Int J Mol Med 2001 Jun;7(6):581-9
ABSTRACT
Friedreich's ataxia is an autosomal recessive neuro-degenerative 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
suggests a 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-European ancestry, has been postulated. Clinical
phenotype is variable and an inverse correlation with the GAA expansion size
has been observed. Analysis of the GAA triplet is a strong molecular
tool for clinical diagnosis, genetic counselling and prenatal diagnosis.
Friedreich's ataxia patho-genesis is not solved 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 oxygen radical affects the oxidative
phosphorylation in frataxin deficiency states favouring the disease
pathology. A second hypothesis postulates a direct role of frataxin in
the mitochondrial energy activation and oxidative phosphorylation. Iron
chelator drugs and antioxidant drugs have been postulated for 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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on lipid
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inhibitory effect of idebenone on vascular lesions in
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