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Review
. 2001 Jul;69(1):15-24.
doi: 10.1086/321283. Epub 2001 Jun 4.

Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency

P I Patel  1 , G Isaya
Affiliations
Review

Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency

P I Patel et al. Am J Hum Genet. 2001 Jul.
No abstract available

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Figures

Figure 1
Figure 1
Proposed models for the formation of non–B DNA conformations by GAA-repeat sequences. A, Intramolecular RRY triplex, formed when the purine-rich strand dissociates from its complementary strand and pairs by Hoogsteen bonding in an antiparallel orientation with the major groove (only one DNA isoform is shown). B, The triplex shown in A, paired with the GAA-containing transcript, thereby further stabilizing the triplex (Bidichandani et al. ; Ohshima et al. 1998). C, A variation in the intramolecular triplex model, in which the wave of negative supercoiling induced by RNA polymerase induces triplex formation, leading to a pause at the promoter distal end of the structure (Grabczyk and Usdin 2000a). Binding of a triplex-forming oligonucleotide (shown in red) to the nontemplate strand can alleviate the transcriptional block by preventing formation of the triplex (Grabczyk and Usdin 2000b). D, Association of two triplexes to form “sticky DNA.” A strand-exchange model is depicted, in which two circular plasmid molecules associate with each other at the RRY triplex regions. The Y strands from the RRY triplexes reassociate with the R looped region from the second triplex and reconfigure to form hybrid RRY triplexes (Sakamoto et al. 1999).
Figure 2
Figure 2
A, Proposed function of frataxin in normal mitochondria. B, Consequences of frataxin deficiency. Ferrochelatase catalyzes the final step of the heme biosynthetic pathway, which involves the insertion of Fe2+ into protoporphyrin IX (IX). This enzyme is localized to the matrix side of the inner mitochondrial membrane and is believed to be able to bind Fe2+ immediately after its reduction by the respiratory chain (Taketani et al. 1986). The initial step in the iron-sulfur (Fe/S) cluster biosynthetic pathway involves Fe2+ binding by the Isu1 and Isu2 proteins, which serve as scaffolds for cluster assembly (Muhlenhoff and Lill 2000). These proteins are localized to the mitochondrial matrix and may depend on frataxin for a sufficient supply of Fe2+. Both decreased biosynthesis and oxidative damage may contribute to Fe/S enzyme defects. ΔΨ = mitochondrial inner-membrane potential.
See this image and copyright information in PMC

References

Electronic-Database Information

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/index.html (for Yfh1p [accession number Q07540] and human frataxin [accession number Q16595])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for FRDA [MIM 229300]) - PubMed

References

    1. Adamec J, Kalousek F, Isaya G (2001) Mitochondrial processing peptidase and mitochondrial intermediate peptidase. In: Dalbey RE, Sigman DS (eds) The enzymes. Academic Press, San Diego
    1. Adamec J, Rusnak F, Owen WG, Naylor S, Benson LM, Gacy AM, Isaya G (2000) Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia. Am J Hum Genet 67:549–562 - PMC - PubMed
    1. Airoldi R, Seveso V, Gellera C, Barisani D, Taroni F (2000) Evidence that human frataxin is assembled in a large multimeric complex in human mitochondria. Am J Hum Genet Suppl 67:395
    1. Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, Pandolfo M, Kaplan J (1997) Regulation of mitochondrial iron accumulation by Yfh1, a putative homolog of frataxin. Science 276:1709–1712 - PubMed
    1. Bidichandani SI, Ashizawa T, Patel PI (1998) The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am J Hum Genet 62:111–121 - PMC - PubMed

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