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Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia.
Nat Genet. 1997 Oct; 17(2):215-7.NGen

Abstract

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.

Authors+Show Affiliations

INSERM U393, Département de Génétique, Hôpital Necker-Enfants-Malades, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9326946

Citation

Rötig, A, et al. "Aconitase and Mitochondrial Iron-sulphur Protein Deficiency in Friedreich Ataxia." Nature Genetics, vol. 17, no. 2, 1997, pp. 215-7.
Rötig A, de Lonlay P, Chretien D, et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997;17(2):215-7.
Rötig, A., de Lonlay, P., Chretien, D., Foury, F., Koenig, M., Sidi, D., Munnich, A., & Rustin, P. (1997). Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nature Genetics, 17(2), 215-7.
Rötig A, et al. Aconitase and Mitochondrial Iron-sulphur Protein Deficiency in Friedreich Ataxia. Nat Genet. 1997;17(2):215-7. PubMed PMID: 9326946.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. AU - Rötig,A, AU - de Lonlay,P, AU - Chretien,D, AU - Foury,F, AU - Koenig,M, AU - Sidi,D, AU - Munnich,A, AU - Rustin,P, PY - 1997/11/5/pubmed PY - 1997/11/5/medline PY - 1997/11/5/entrez SP - 215 EP - 7 JF - Nature genetics JO - Nat Genet VL - 17 IS - 2 N2 - 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. SN - 1061-4036 UR - https://www.unboundmedicine.com/medline/citation/9326946/Aconitase_and_mitochondrial_iron_sulphur_protein_deficiency_in_Friedreich_ataxia_ L2 - https://doi.org/10.1038/ng1097-215 DB - PRIME DP - Unbound Medicine ER -