Friedreichs Ataxia

Friedreich's ataxia (FRDA) is an adolescent-onset ataxia, associated with clumsiness in walking, which is accompanied by sensory loss, curvature of the spine, foot deformity and heart disease [132]. It is one of 15 neurological diseases in man which are known to be caused by the anomalous expansion of unstable trinucleotide repeats. However, in FRDA, the trinucleotide expansion occurs in a non-coding region of the gene (Figure 21). FRDA was found to be due to an expanded trinucleotide repeat (GAA) within the first intron of the gene for a 210 residue mitochondrial protein named frataxin [133]. Frataxin protein levels are severely decreased in FRDA patients. In FRDA patients, the first intron of the frataxin gene contains between 90 and 1700 GAA units. Most normal alleles carry six to nine GAA repeats, and never more than 34 repeats [133-135]. The expansion of this GAA trinucleotide repeat severely decreases the expression of the frataxin protein, reducing the quantity of frataxin mRNA produced. It has been suggested that the GAA-rich sequence is 'sticky' DNA, which forms a triple-helical structure, and impedes the transcription of the gene by RNA polymerase [136]. The three-dimensional structure of human frataxin consists of a stable seven-stranded antiparallel P-sheet packed against a pair of parallel a-helices (Figure 22) [137]. The recently determined solution structure of the yeast protein confirms this [138].

There has been considerable debate on the role of frataxin in iron metabolism, but, by far the most promising hypothesis is that frataxin is required for

Truncating mutations

Truncating mutations

Figure 21. Frataxin mutations. The commonest mutation is the GAA expansion in the first intron of the frataxin gene (98% of cases). Boxes represent exons and bars represent introns of the frataxin gene. Asterisks indicate the number of families reported for each of the other mutations. (Reproduced with permission from [172]).

Figure 22. Structure of frataxin. Ribbon diagram showing the fold of frataxin, a compact aP sandwich with a-helices and P-strands. Strands pi—P5 form a large flat antiparallel P-sheet, which interacts with the two helices a1 and a2. The two helices are almost parallel to one another and to the plane of the large P-sheet. A second smaller P-sheet is formed by the C-terminus of P5 and strands P6 and P7. (Reproduced with permission from [137]).

Figure 22. Structure of frataxin. Ribbon diagram showing the fold of frataxin, a compact aP sandwich with a-helices and P-strands. Strands pi—P5 form a large flat antiparallel P-sheet, which interacts with the two helices a1 and a2. The two helices are almost parallel to one another and to the plane of the large P-sheet. A second smaller P-sheet is formed by the C-terminus of P5 and strands P6 and P7. (Reproduced with permission from [137]).

iron-sulfur cluster biosynthesis, and also for heme biosynthesis. A role for frataxin in iron-sulfur cluster assembly was supported by the finding of reduced levels of iron-sulfur proteins in FRDA patients as well as in yeast and mouse frataxin-deficient models [139-142]. Frataxin appears to play an important role in this process in yeast. It is necessary for assembly of the iron-sulfur cluster into yeast ferredoxin [143] and it interacts both in vivo [144] and in vitro [145,146] with the iron-sulfur cluster scaffold proteins Isul. Isul which, together with the cysteine desulfurase Nfs1, constitute the central Fe-S assembly complex. It seems reasonable to assume that frataxin supplies iron to this complex for Fe-S cluster assembly, as has been shown by in vitro experiments [146,147].

Yeast cells which lack frataxin show low content of cytochromes, and it has been suggested from genetic studies [148] and from in vitro studies with iron-containing frataxin and ferrochelatase, the enzyme which inserts iron into protoporphyrin IX [138,149,150] that frataxin may also be the donor of iron for heme synthesis.

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