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Gene Review

Fxn  -  frataxin

Mus musculus

Synonyms: FA, FARR, Frataxin, mitochondrial, Frda, X25
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Disease relevance of Fxn

  • Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation [1].
  • Friedreich ataxia (FRDA), the most common autosomal recessive inherited ataxic disorder, is the consequence of deficiency of the mitochondrial protein frataxin, typically caused by homozygous intronic GAA expansions in the corresponding gene [2].
  • Our studies indicate an association between frataxin deficiency, iron deposits and cardiac fibrosis, but no obvious association between iron accumulation and neurodegeneration similar to FRDA could be detected in our model [2].
  • In addition, these results suggest that frataxin mutations may have a modifier role in HH, that predisposes to cardiomyopathy [2].
  • A mutant allele (X25) of an essential regulatory protein, ICP4, encoded by herpes simplex virus (HSV) has been shown to have a transdominant, negative effect on the activity of the wild-type protein, resulting in the inhibition of virus growth in vitro [3].

High impact information on Fxn


Biological context of Fxn

  • These results suggest that the milder phenotype in humans is due to residual frataxin expression associated with the expansion mutations [6].
  • We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation [7].
  • Our results support the view that frataxin is a necessary, albeit non-essential, component of the Fe-S cluster biogenesis, and indicate that Idebenone acts downstream of the primary Fe-S enzyme deficit [8].
  • Surprisingly, in the frataxin knockout mouse, no iron accumulation was observed during embryonic resorption, suggesting that cell death could be due to a mechanism independent of iron accumulation [6].
  • Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin [7].

Anatomical context of Fxn

  • Normal spleen cells were fractionated on a Percoll density gradient and two fractions were examined: fraction (Fxn) 3, which is enriched for NK activity but depleted of the ability to generate cytotoxic T lymphocytes (CTL), and Fxn 5, which had no NK activity but was enriched for the ability to generate CTL [9].
  • We now demonstrate that overexpression of frataxin in mammalian cells causes a Ca(2+)-induced up-regulation of tricarboxylic acid cycle flux and respiration, which, in turn, leads to an increased mitochondrial membrane potential (delta psi(m)) and results in an elevated cellular ATP content [5].
  • Hybrid molecules were constructed between the M460 proteins and the products of 2 myelomas that do not activate B cells, namely, X25 and X24 [10].
  • Cytoplasmic F-actin (FA) also increased transiently coincident with the enhancement of stress fibers [11].
  • These findings concerning actin polymerization and FA gelation suggest that the alteration of stress fibers in cultured cells is caused by a direct effect of D2O on cellular MF dynamics [11].

Associations of Fxn with chemical compounds

  • It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis [12].
  • Response to parenteral iron challenge was not different between Fx(+/-) mice and wild type littermates, while sporadic iron deposits were observed in the hearts of dietary iron-loaded Fx(+/-) mice [2].
  • Neighboring tyrosine and serine residues were mutated to either phenylalanine and alanine (mutant YS/FA) or valine and valine (mutant YS/VV) [13].

Regulatory relationships of Fxn

  • Moreover, we demonstrate that complete frataxin-deficiency neither induces oxidative stress in neuronal tissues nor alters the MnSOD expression and induction in the early step of the pathology (neuronal and cardiac) as previously suggested [14].

Other interactions of Fxn

  • Iron concentrations in the liver, heart, pancreas and spleen, and cellular iron distribution patterns were compared between wild type and Fx(+/-) mice [2].

Analytical, diagnostic and therapeutic context of Fxn


  1. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Puccio, H., Simon, D., Cossée, M., Criqui-Filipe, P., Tiziano, F., Melki, J., Hindelang, C., Matyas, R., Rustin, P., Koenig, M. Nat. Genet. (2001) [Pubmed]
  2. Iron metabolism in mice with partial frataxin deficiency. Santos, M.M., Miranda, C.J., Levy, J.E., Montross, L.K., Cossée, M., Sequeiros, J., Andrews, N., Koenig, M., Pandolfo, M. Cerebellum (2003) [Pubmed]
  3. Transdominant inhibition of herpes simplex virus growth in transgenic mice. Smith, C.A., DeLuca, N.A. Virology (1992) [Pubmed]
  4. Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass. Ristow, M., Mulder, H., Pomplun, D., Schulz, T.J., Müller-Schmehl, K., Krause, A., Fex, M., Puccio, H., Müller, J., Isken, F., Spranger, J., Müller-Wieland, D., Magnuson, M.A., Möhlig, M., Koenig, M., Pfeiffer, A.F. J. Clin. Invest. (2003) [Pubmed]
  5. Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Ristow, M., Pfister, M.F., Yee, A.J., Schubert, M., Michael, L., Zhang, C.Y., Ueki, K., Michael, M.D., Lowell, B.B., Kahn, C.R. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Cossée, M., Puccio, H., Gansmuller, A., Koutnikova, H., Dierich, A., LeMeur, M., Fischbeck, K., Dollé, P., Koenig, M. Hum. Mol. Genet. (2000) [Pubmed]
  7. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Thierbach, R., Schulz, T.J., Isken, F., Voigt, A., Mietzner, B., Drewes, G., von Kleist-Retzow, J.C., Wiesner, R.J., Magnuson, M.A., Puccio, H., Pfeiffer, A.F., Steinberg, P., Ristow, M. Hum. Mol. Genet. (2005) [Pubmed]
  8. Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia. Seznec, H., Simon, D., Monassier, L., Criqui-Filipe, P., Gansmuller, A., Rustin, P., Koenig, M., Puccio, H. Hum. Mol. Genet. (2004) [Pubmed]
  9. Lymphokine-activated killer (LAK) cells. II. Delineation of distinct murine LAK-precursor subpopulations. Ballas, Z.K., Rasmussen, W., van Otegham, J.K. J. Immunol. (1987) [Pubmed]
  10. Recognition of MOPC-460 variable region determinants by polyclonally distributed triggering receptors on B lymphocytes. Primi, D., Juy, D., Le Guern, C., Sanchez, P., Cazenave, P.A. J. Immunol. (1981) [Pubmed]
  11. Deuterium oxide (heavy water) accelerates actin assembly in vitro and changes microfilament distribution in cultured cells. Omori, H., Kuroda, M., Naora, H., Takeda, H., Nio, Y., Otani, H., Tamura, K. Eur. J. Cell Biol. (1997) [Pubmed]
  12. Friedreich ataxia mouse models with progressive cerebellar and sensory ataxia reveal autophagic neurodegeneration in dorsal root ganglia. Simon, D., Seznec, H., Gansmuller, A., Carelle, N., Weber, P., Metzger, D., Rustin, P., Koenig, M., Puccio, H. J. Neurosci. (2004) [Pubmed]
  13. A mutation of the mu transmembrane that disrupts endoplasmic reticulum retention. Effects on association with accessory proteins and signal transduction. Stevens, T.L., Blum, J.H., Foy, S.P., Matsuuchi, L., DeFranco, A.L. J. Immunol. (1994) [Pubmed]
  14. Friedreich ataxia: the oxidative stress paradox. Seznec, H., Simon, D., Bouton, C., Reutenauer, L., Hertzog, A., Golik, P., Procaccio, V., Patel, M., Drapier, J.C., Koenig, M., Puccio, H. Hum. Mol. Genet. (2005) [Pubmed]
  15. Evaluation of an FRDA-EGFP genomic reporter assay in transgenic mice. Sarsero, J.P., Holloway, T.P., Li, L., McLenachan, S., Fowler, K.J., Bertoncello, I., Voullaire, L., Gazeas, S., Ioannou, P.A. Mamm. Genome (2005) [Pubmed]
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