Aconitase and mitochondrial iron–sulphur protein deficiency in Friedreich ataxia (original) (raw)

Nature Genetics volume 17, pages 215–217 (1997)Cite this article

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 limbs1,2. 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 alleles4. The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA patients5 and in mitochondria of yeast strains carrying a deleted frataxin gene counterpart (YFH1), suggesting that frataxin plays a major role in regulating mitochondria! iron transport6,7. 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 radicals8. Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA, which should therefore be regarded as a mitochondrial disorder.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Geoffroy, G. et al. Clinical description and roentgenologic evaluation of patients with Friedreich's ataxia. Can. J. Neurol. Sci. 3, 279–286 (1976).
    Article CAS PubMed Google Scholar
  2. Harding, A.E. Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 104, 598–620 (1981).
    Article Google Scholar
  3. Chamberlain, S. et al. Genetic homogeneity of the Friedreich ataxia locus on chromosome 9. Am. J. Hum. Genet. 44, 518–521 (1989).
    CAS PubMed PubMed Central Google Scholar
  4. Campuzano, V. et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).
    Article CAS PubMed Google Scholar
  5. Sanchez-Casis, G., Cote, M. & Barbeau, A. Pathology of the heart in FriedreichS ataxia: review of the literature and report of one case. Can. J. Neurol. Sci. 3, 349–354 (1977).
    Article Google Scholar
  6. Babcock, M. et al. Regulation of mitochondrial iron accumulation by Yfhlp, a putative homolog of frataxin. Science 276, 1709–1712 (1997).
    Article CAS PubMed Google Scholar
  7. Foury, F. & Cazzalini, O. Deletion of the yeast homologue of the human gene associated with Friedreich's ataxia elicits iron accumulation in mitochondria. FEBS Lett. 411, 373–377 (1997).
    Article CAS PubMed Google Scholar
  8. Fridovitch, I. Superoxide radical and superoxide dismutases. Annu. Rev. Biochem. 64, 97–112 (1995).
    Article Google Scholar
  9. Cedarbaum, J.M. & Blass, J.P. Mitochondrial dysfunction and spinocerebellar degenerations. Neurochem. Pathol. 4, 43–63 (1986).
    Article CAS PubMed Google Scholar
  10. Koutnitkova, H. et al. Studies of human, mouse and yeast homologues indicate a mitochondrial function for the frataxin. Nature Genet. 16, 345–351 (1997).
    Article Google Scholar
  11. Rustin, P. et al. Endomyocardial biopsy for early detection of mitochondrial disorders in hypertrophiccardiomyopathies. J. Pediatr. 124, 224–228 (1994).
    Article CAS PubMed Google Scholar
  12. Rustin, P. et al. Assessment of the mitochondrial respiratory chain (letter). Lancet 338, 60 (1991).
    Article CAS PubMed Google Scholar
  13. Jacq, C. et al. The nucleotide sequence of Saccharomyces cerevisiae chromosome IV. Nature 387 (Suppl) 75–78 (1997).
    CAS PubMed Google Scholar
  14. Kaptain, S. et al. A regulated RNA binding protein also possesses aconitase activity. Proc. Natl. Acad Sci. USA 88, 10109–10113 (1991).
    Article CAS PubMed PubMed Central Google Scholar
  15. Hentze, M.W. & Kühn, L.C. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl. Acad. Sci. USA 93, 8175–8182 (1996).
    Article CAS PubMed PubMed Central Google Scholar
  16. Li, Y. et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nature Genet. 11, 376–381 (1996).
    Article Google Scholar
  17. Filla, A. et al. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am. J. Hum. Genet. 59, 554–560 (1996).
    CAS PubMed PubMed Central Google Scholar
  18. Paul, R., Santucci, S., Saunières, A., Desnuelle, C. & Paquis-Flucklinger, V. Rapid mapping of mitochondrial DNA deletions by large fragment PCR. Trends Genet. 12, 131–132 (1996).
    CAS PubMed Google Scholar
  19. Rickwood, D., Wilson, M.T. & Darley-Usmar, V.M. Isolation and characteristics of intact mitochondria, in Mitochondria: A Practical Approach (eds Darley-Usmar, V. M., Rickwood, D. & Wilson, M.T.) 1–16 (IRL, Oxford, UK, (1987).
    Google Scholar
  20. Rustin, P. et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin. Chim. Acta 228, 35–51 (1994).
    Article CAS PubMed Google Scholar
  21. Robinson, J.B., Brent, L.G., Sumegi, B. & Srere, P.A. An enzymatic approach to the study of the Krebs tricarboxylic acid cycle, in Mitochondria: A Practical Approach (eds Darley-Usmar, V. M., Rickwood, D. & Wilson, M.T.) 153–170 (IRL, Oxford, UK, (1987).
    Google Scholar

Download references

Author information

Authors and Affiliations

  1. INSERM U393, Département de Génétique and Département de Pédiatrie, Hôpital Necker-Enfants-Malades, 149 rue de Sèvres, 75743, Paris, Cedex 15, France
    Agnès Rötig, Pascale de Lonlay, Dominique Chretien, Daniel Sidi, Arnold Munnich & Pierre Rustin
  2. Unité de Biochimie Physiologique, Université Catholique deLouvain, 1348, Louvain-la-Neuve, Belgium
    Françoise Foury
  3. Institutde Génétique et de Biologie Moléculaire et Cellulaire, INSERM, CNRS, 1 rue Laurent Fries, BP 163, 67404, Illkirch, France
    Michel Koenig

Authors

  1. Agnès Rötig
    You can also search for this author inPubMed Google Scholar
  2. Pascale de Lonlay
    You can also search for this author inPubMed Google Scholar
  3. Dominique Chretien
    You can also search for this author inPubMed Google Scholar
  4. Françoise Foury
    You can also search for this author inPubMed Google Scholar
  5. Michel Koenig
    You can also search for this author inPubMed Google Scholar
  6. Daniel Sidi
    You can also search for this author inPubMed Google Scholar
  7. Arnold Munnich
    You can also search for this author inPubMed Google Scholar
  8. Pierre Rustin
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toArnold Munnich.

Rights and permissions

About this article

Cite this article

Rötig, A., de Lonlay, P., Chretien, D. et al. Aconitase and mitochondrial iron–sulphur protein deficiency in Friedreich ataxia.Nat Genet 17, 215–217 (1997). https://doi.org/10.1038/ng1097-215

Download citation