Entry - *606829 - FRATAXIN; FXN

Frataxin is a nuclear-encoded mitochondrial iron chaperone involved in iron-sulfur biogenesis and heme biosynthesis. Some studies have also suggested that frataxin functions as an iron storage molecule, an antioxidant, and a tumor suppressor (summary by Schmucker et al. (2008)).

▼ Cloning and Expression

By searching the candidate region defined by analysis of recombination events in families with Friedreich ataxia (FRDA; 229300), Montermini et al. (1995) reported that they had located a 150-kb region in chromosome 9q13 that represented the FRDA locus. Campuzano et al. (1996) identified potential exons in the region in chromosome 9q13 using cDNA selection and sequence analysis. The FXN gene was isolated by this method and called X25 by the authors. It encodes a 210-amino acid protein, termed frataxin. It was shown to be expressed in a range of tissues, most abundantly in heart. High levels of expression were also found in the spinal cord; lower levels were detected in the cerebellum, and no expression was demonstrated in the cerebral cortex.

Koutnikova et al. (1997) cloned the complete coding region of mouse frataxin and studied its pattern of expression in developing and adult tissues. Frataxin mRNA was predominantly expressed in tissues with a high metabolic rate, including liver, kidney, brown fat, and heart. They showed that mouse and yeast frataxin homologs contain a potential mitochondrial targeting sequence in their N-terminal domains and that disruption of the yeast gene results in mitochondrial dysfunction.

▼ Gene Structure

Campuzano et al. (1996) found that the FXN gene contains 6 exons.

Baralle et al. (2008) stated that the FXN gene contains 7 exons and spans about 80 kb. The GAA repeat, which when expanded is associated with disease, is located in the middle of an Alu sequence in the approximately 11-kb first intron.

▼ Mapping

By sequence analysis, Campuzano et al. (1996) mapped the FXN gene to chromosome 9q13.

▼ Gene Function

To study frataxin function, Campuzano et al. (1997) developed monoclonal antibodies raised against different regions of the frataxin protein. These antibodies detected a processed 18-kD protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy, Campuzano et al. (1997) demonstrated that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targeting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency, and some mitochondriopathies, Campuzano et al. (1997) suggested that their data indicate that a reduction in frataxin results in oxidative damage.

Using the yeast 2-hybrid assay (Fields and Song, 1989), Koutnikova et al. (1998) identified mitochondrial processing peptidase-beta (MPPB; 603131) as a frataxin protein partner. In in vitro assays, MPPB bound frataxin which is cleaved by the reconstituted MPP heterodimer. MPP cleavage of frataxin results in an intermediate form (amino acids 41 to 210) that is processed further to the mature form. In vitro and in vivo experiments suggested that 2 C-terminal missense mutations found in FRDA patients, I151F (606829.0004) and G127V (606829.0005), modulate interaction with MPP-beta, resulting in a slower maturation process at the normal cleavage site. The slower processing rate of frataxin carrying such missense mutations may therefore contribute to frataxin deficiency, in addition to an impairment of its function. Similar studies were reported by Gordon et al. (1999), with conflicting results. They performed in vitro experiments with MPP, wildtype and I154F human frataxin or its mutant yeast homolog, and purified mammalian or yeast mitochondria. These authors concluded that MPP was capable of 1-step processing of frataxin to the mature form, and that the I154F mutation had no effect on mitochondrial import and/or maturation of frataxin.

Schmucker et al. (2008) found that the 210-amino acid FXN precursor could be processed into several forms in vitro depending upon the assay conditions. They determined that the physiologically relevant mature peptide corresponds to amino acids 81 through 210, which is generated by MPPB in 2 cleavage steps.

Ristow et al. (2000) demonstrated that overexpression of frataxin in mammalian cells causes a Ca(2+)-induced upregulation of tricarboxylic acid cycle flux and respiration, which, in turn, leads to an increased mitochondrial membrane potential and results in an elevated cellular ATP content. Thus, frataxin appears to be a key activator of mitochondrial energy conversion and oxidative phosphorylation.

Santos et al. (2001) examined the role of frataxin in neuronal differentiation by transfecting the P19 embryonic carcinoma cell line with antisense or sense frataxin constructs. During retinoic acid-induced neurogenesis of frataxin-deficient cells there was a striking rise in cell death, while cell division remained unaffected. However, frataxin deficiency did not affect cell survival in cells induced to differentiate into cardiomyocytes. Frataxin deficiency enhanced apoptosis of retinoic acid-stimulated cells, and the number of neuronal-like cells expressing MAP2 (157130) was dramatically reduced in these clones. In addition, antisense clones induced to differentiate into neuroectoderm with retinoic acid had increased production of reactive oxygen species, and only cells noncommitted to the neuronal lineages could be rescued by the addition of the antioxidant N-acetylcysteine (NAC). However, NAC treatment had no effect in increasing the number of terminally differentiated neuronal-like cells in frataxin-deficient clones. The authors suggested that frataxin deficiency may render cells susceptible to apoptosis after exposure to appropriate stimuli.

Adinolfi et al. (2002) compared the properties of 3 proteins from the frataxin family (bacterial CyaY from Escherichia coli, yeast Yfh1, and human frataxin) as representative of organisms of increasing complexity. The 3 proteins have the same fold but different thermal stabilities and iron-binding properties. While human frataxin has no tendency to bind iron, CyaY forms iron-promoted aggregates with a behavior similar to that of yeast frataxin. Mutants produced to identify the protein surface involved in iron-promoted aggregation demonstrated that the process is mediated by a negatively charged surface ridge. Mutation of 3 of these residues was sufficient to convert CyaY into a protein with properties similar to those of human frataxin. On the other hand, mutation of the exposed surface of the beta sheet, which contains most of the conserved residues, did not affect aggregation, suggesting to the authors that iron binding is a nonconserved part of a more complex cellular function of frataxins.

Cavadini et al. (2002) showed that the mature form of human frataxin, when expressed in E. coli, assembles into a stable homopolymer that can bind approximately 10 atoms of iron per molecule of frataxin. As analyzed by gel filtration and electron microscopy, the homopolymer consists of globular particles of approximately 1 megadalton and orders rod-shaped polymers of these particles that accumulate small electron-dense cores. When the human frataxin precursor was expressed in S. cerevisiae, the mitochondrially-generated mature form was separated by gel filtration into monomer and a high molecular weight pool of approximately 600 kD, which was also present in mouse heart. In radiolabeled yeast cells, human frataxin was recovered by immunoprecipitation with approximately 5 atoms of iron bound per molecule. The authors suggested that FRDA may result from decreased mitochondrial iron storage due to frataxin deficiency, which may impair iron metabolism, promote oxidative damage, and lead to progressive iron accumulation.

Shoichet et al. (2002) demonstrated that transgenic overexpression of human frataxin in murine 3T3-L1 cells increased cellular antioxidant defense. Subsequent activation of glutathione peroxidase and elevation of reduced thiols reduced the incidence of malignant transformation induced by reactive oxygen species, as observed by tumor formation in nude mice. The authors tentatively suggested a role for frataxin mutations in the early induction of cancer.

Tan et al. (2003) analyzed gene expression in 3 human cell types using microarrays and identified 48 transcripts whose expression was significantly frataxin-dependent in at least 2 cell types. Significant decreases in 7 transcripts occurred in the sulfur amino acid (SAA) biosynthetic pathway and the iron-sulfur cluster (ISC) biosynthetic pathway to which it is connected. Expression of ISC-S and rhodanese (TST; 180370) transcripts was lower in mutants. Homocystine, cysteine, cystathionine, and serine were significantly decreased in frataxin-deficient cell extracts and mitochondria. Succinate dehydrogenase and aconitase, whose activities require ISCs, were less active. The ISC-U scaffold protein was specifically decreased in frataxin-deficient cells, and sodium sulfide partially rescued the oxidant sensitivity of the FRDA cells. Multiple transcripts involved in the Fas (134637)/TNF (191160)/interferon apoptosis pathway were upregulated in frataxin-deficient cells, consistent with a multistep mechanism of Friedreich ataxia pathophysiology and suggesting alternative possibilities for therapeutic intervention.

By RNA interference (RNAi) of frataxin in HeLa cells, Stehling et al. (2004) found that the enzyme activity of mitochondrial Fe/S proteins aconitase (ACO1/IRP1; 100880) and succinate dehydrogenase (SDHA; 600857) was decreased, while the activity of non-Fe/S proteins remained constant. Fe/S cluster association with cytosolic IRP1 was diminished. In contrast, no alterations in cellular iron uptake, iron content, and heme formation were found, and no mitochondrial iron deposits were observed upon frataxin depletion. Iron accumulation in FRDA mitochondria appeared to be a late consequence of frataxin deficiency. Stehling et al. (2004) concluded that frataxin is a component of the human Fe/S cluster assembly machinery and that it plays a role in the maturation of both mitochondrial and cytosolic Fe/S proteins.

Bulteau et al. (2004) found that aconitase (100850) activity can undergo reversible citrate-dependent modulation in response to prooxidants. Frataxin interacted with aconitase in a citrate-dependent fashion, reduced the level of oxidant-induced inactivation, and converted the inactive [3Fe-4S]1+ enzyme to the active [4Fe-4S]2+ form of the protein. Bulteau et al. (2004) concluded that frataxin is an iron chaperone protein that protects the aconitase [4Fe-4S]2+ cluster from disassembly and promotes enzyme reactivation.

To further discern the role of oxidative stress in FRDA pathophysiology, Seznec et al. (2005) tested the potential effect of increased antioxidant defense using an MnSOD mimetic (SOD2; 147460) and Cu-Zn SOD (SOD1; 147450) overexpression on murine FRDA cardiomyopathy. No positive effect was observed, suggesting that increased superoxide production could not solely explain the cardiac pathophysiology associated with FRDA. Complete frataxin deficiency neither induced oxidative stress in neuronal tissues nor altered MnSOD expression and induction in early stages of neuronal and cardiac pathology. Cytosolic ISC aconitase activity of IRP1 progressively decreased, whereas its apo-RNA binding form increased despite the absence of oxidative stress, suggesting that in a mammalian system the mitochondrial ISC assembly machinery is essential for cytosolic ISC biogenesis. Seznec et al. (2005) concluded that in FRDA, mitochondrial iron accumulation does not induce oxidative stress, and FRDA is not associated with oxidative damage.

By immunoprecipitation analysis of mitochondria from human lymphoblasts and transfected COS-7 cells, Shan et al. (2007) showed that FXN interacted directly with several mitochondrial proteins, including the iron-sulfur cluster biogenesis complex component ISD11 (LYRM4; 613311), the mitochondrial chaperones HSPA9 (600548) and HSP60 (HSPD1; 118190), the ATP synthase subunit ATP5L, the ATPase ATAD3A (612316), succinate dehydrogenase subunit A (SDHA; 600857), AFG3L2 (604581), and FXN itself. Reciprocal immunoprecipitation analysis confirmed the interactions of FXN with ISD11 and HSPA9 in transfected HEK293 cells. The interaction between FXN and ISD11 was reversed by EDTA and by several cations at physiologic concentration, including Fe(3+). However, Ni(2+) strengthened the interaction between FXN and ISD11. RT-PCR analysis of lymphoblasts from Friedreich ataxia patients revealed that reduced FXN mRNA was associated with reduced ISD11 mRNA. Shan et al. (2007) proposed that FXN deficiency causes transcriptional corepression of genes involved in iron-sulfur cluster biosynthesis.

Using various binding assays, Dong et al. (2019) showed that Grp75 (HSPA9) bound directly to frataxin, preferentially to the frataxin precursor, in mouse brain cortex and neuronal cells. Grp75 also interacted with Mpp (613036) and potentiated interaction of Mpp with frataxin, which facilitated frataxin maturation. Frataxin deficiency in FRDA cells correlated with GRP75 reduction, but frataxin overexpression or knockdown had no effect on GRP75 expression in HEK293 cells and human skin fibroblasts. These findings suggested that GRP75 reduction in FRDA patient cells was due to a chronic, secondary effect of frataxin deficiency rather than a direct effect. GRP75 overexpression increased proteins levels of wildtype frataxin and frataxin mutants in HEK293 cells, whereas Parkinson disease-associated GRP75 loss-of-function mutants reduced expression of frataxin and binding of GRP75 to frataxin. Both mitochondria-targeted GRP75 and cytosolic GRP75 overexpression increased frataxin and rescued ATP deficit in FRDA patient cells. However, only mitochondria-targeted GRP75 expression rescued abnormalities of mitochondrial morphology in FRDA patient cells.

Using hybrid reporter minigenes with 100 GAA or TTC repeats transfected into COS or HeLa cells, Baralle et al. (2008) found that both repeats were efficiently transcribed and inserted into nascent pre-mRNAs that bound multiple splicing factors. However, the GAA repeats, but not TTC repeats, caused aberrant splicing of the pre-mRNA. The type of aberrant splicing depended on the position used for insertion of the GAA repeat, and the length of the repeat affected the severity of the splicing abnormality. GAA repeats inserted in a frataxin minigene reduced splicing efficiency without affecting the abundance of the nascent transcript. The pathologic expansion induced a block in the processing of 1 splicing intermediate that accumulated in the nucleus. Baralle et al. (2008) proposed that the block caused by GAA expansion results from interference from multiple splicing factors bound to the nascent GAA repeat-containing transcript, resulting in degradation of the pre-RNA and lower abundance of mature frataxin mRNA.

To address the physiologic function of human extramitochondrial frataxin, Condo et al. (2010) searched for ISC-dependent interaction partners. The authors demonstrated that the extramitochondrial form of frataxin directly interacted with cytosolic aconitase/iron regulatory protein-1 (ACO1/IRP1; 100880), a bifunctional protein alternating between an enzymatic and an RNA-binding function through the 'iron-sulfur switch' mechanism. The cytosolic aconitase defect and consequent IRP1 activation occurring in FRDA cells were reversed by the action of extramitochondrial frataxin.

Studies Using the Yeast Frataxin Homolog

Babcock et al. (1997) characterized a gene in Saccharomyces cerevisiae whose predicted gene product had high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein.

Wilson and Roof (1997) showed that YFH1 localizes to mitochondria and is required to maintain mitochondrial DNA. They showed that the YFH1-homologous domain of frataxin functions in yeast and that a disease-associated missense mutation of this domain, or the corresponding domain in YFH1, reduces function.

Adamec et al. (2000) expressed a mature form of the YFH1 protein in E. coli and analyzed its function in vitro. The isolated protein is a soluble monomer that contains no iron and shows no significant tendency to self-associate. Aerobic addition of ferrous iron to the protein resulted in assembly of regular spherical multimers. Each multimer consists of approximately 60 subunits and can sequester more than 3,000 atoms of iron. Titration of the yeast protein with increasing iron concentrations supported a stepwise mechanism of multimer assembly. Sequential addition of an iron chelator and a reducing agent resulted in quantitative iron release with concomitant disassembly of the multimer, indicating that the yeast frataxin protein sequesters iron in an available form. Adamec et al. (2000) proposed that iron-dependent self-assembly of recombinant yeast frataxin protein reflects a physiologic role for frataxin in mitochondrial iron sequestration and bioavailability.

Cavadini et al. (2000) showed that wildtype FRDA cDNA can complement the YFH1 protein-deficient yeast (YFH1-delta) by preventing the mitochondrial iron accumulation and oxidative damage associated with loss of YFH1. The G130V mutation (606829.0005) affected protein stability and resulted in low levels of mature frataxin, which were nevertheless sufficient to rescue YFH1-delta yeast. The W173G (606829.0007) mutation affected protein processing and stability and resulted in severe mature frataxin deficiency. Expression of the FRDA W173G cDNA in YFH1-delta yeast led to increased levels of mitochondrial iron which were not as elevated as in YFH1-deficient cells but were above the threshold for oxidative damage of mitochondrial DNA and iron-sulfur centers, causing a typical YFH1-delta phenotype. The authors concluded that frataxin functions like YFH1 protein, providing additional experimental support for the hypothesis that FRDA is a disorder of mitochondrial iron homeostasis.

Gordon et al. (2001) mapped the 2 cleavage sites of the YFH1 protein precursor. Mutations blocking the first or the second cleavage of YFH1 protein did not interfere with its import from the cytoplasm or with its ability to complement phenotypes of the YFH1-delta mutant yeast strain. The first cleaved domain (domain I), consisting of 20 N-terminal amino acids, was able to import a nonmitochondrial passenger fusion protein. However, neither domain I nor other matrix-targeting signals alone could support efficient import of mature YFH1 protein. The second cleaved domain (domain II), consisting of an additional 31 N-terminal amino acids, was required as a spacer between a targeting signal and mature YFH1 protein. Likewise, when YFH1 protein constructs lacking domain I or II were expressed in vivo, they failed to attain appreciable steady-state amounts in mitochondria and could not complement phenotypes of the YFH1-delta mutant.

Karthikeyan et al. (2002) found that the absence of frataxin in yeast leads to nuclear damage, as evidenced by inducibility of a nuclear DNA damage reporter, increased chromosomal instability including recombination and mutation, and greater sensitivity to DNA-damaging agents, as well as slow growth. Addition of a human frataxin mutant did not prevent nuclear damage, although it partially complemented the YFH1 mutant in preventing mitochondrial DNA loss. The effects in YFH1 mutants appeared to result from reactive oxygen species, since (1) YFH1 cells produce more hydrogen peroxide, (2) the effects are alleviated by the radical scavenger N-acetylcysteine, and (3) the glutathione peroxidase gene (GPX1; 138320) prevents an increase in mutation rates. The authors concluded that the frataxin protein has a protective role for the nucleus as well as the mitochondria.

Muhlenhoff et al. (2002) constructed a yeast strain (Gal-YFH1) that carried the YFH1 gene under the control of a galactose-regulated promoter. Yfh1p-deficient Gal-YFH1 cells were far less sensitive to oxidative stress than delta-yfh1 mutants, maintained mitochondrial DNA, and synthesized heme at wildtype rates. Yfh1p depletion caused a strong reduction in the assembly of mitochondrial Fe/S proteins, which may explain the respiratory deficiency of Gal-YFH1 cells. Yfh1p-depleted Gal-YFH1 cells show decreased maturation of cytosolic Fe/S proteins and accumulation of mitochondrial iron, which may be seen secondary to defects in cytosolic Fe/S protein assembly. The authors proposed a specific role of frataxin in the biosynthesis of cellular Fe/S proteins which excluded most of the previously suggested functions.

Saccharomyces cerevisiae cells lacking the Yfh1 gene showed very low cytochrome content. Lesuisse et al. (2003) showed that in delta-yfh1 strains, the level of ferrochelatase (612386) was very low as a result of transcriptional repression of HEM15. However, the low amount of ferrochelatase was not the cause of heme deficiency in delta-yfh1 cells. Ferrochelatase, a mitochondrial protein able to mediate insertion of iron or zinc into the porphyrin precursor, made primarily the zinc protoporphyrin product. Yfh1p and ferrochelatase were shown to interact in vitro by BIAcore studies. Lesuisse et al. (2003) concluded that Yfh1 mediates iron use by ferrochelatase.

Karthikeyan et al. (2003) developed a highly regulatable promoter system for expressing frataxin in yeast to address the consequences of chronically reduced amounts of this protein. Shutting off the promoter resulted in changes normally associated with loss of frataxin, including iron accumulation within the mitochondria and the induction of mitochondrial 'petite' phenotype mutants. While there was considerable oxidative damage to mitochondrial proteins, the 'petites' were likely due to accumulation of mitochondrial DNA lesions and subsequent DNA loss. Chronically reduced frataxin levels resulted in similar response patterns. Furthermore, nuclear DNA damage was detected in a rad52 (see 600392) mutant, deficient in double-strand break repair. Karthikeyan et al. (2003) concluded that reduced frataxin levels, which may be more representative of the disease state in Friedreich ataxia, resulted in considerable oxidative damage in both mitochondrial and nuclear DNA.

Campanella et al. (2004) expressed human mitochondrial ferritin (FTMT; 608847) in frataxin-deficient yeast cells. The human FTMT precursor was efficiently imported by yeast mitochondria and processed to functional ferritin that actively sequestered iron in the organelle. FTMT expression rescued the respiratory deficiency caused by the loss of frataxin protecting the activity of iron-sulfur enzymes and enabling frataxin-deficient cells to grow on nonfermentable carbon sources. Furthermore, FTMT expression prevented the development of mitochondrial iron overload, preserved mitochondrial DNA integrity, and increased cell resistance to H2O2. Campanella et al. (2004) concluded that FTMT can substitute for most frataxin functions in yeast, suggesting that frataxin may be directly involved in mitochondrial iron-binding and detoxification.

Gonzalez-Cabo et al. (2005) showed that Yfh1 interacted physically with succinate dehydrogenase complex subunits Sdh1 (SDHA; 600857) and Sdh2 (SDHB; 185470) of the yeast mitochondrial electron transport chain and also with electron transfer flavoprotein complex ETF-alpha (608053) and ETF-beta (130410) subunits from the electron transfer flavoprotein complex. Genetic synthetic interaction experiments confirmed a functional relationship between Yfh1 and Sdh1/Sdh2, and coimmunoprecipitation showed physical interaction between human frataxin and SDH1/SDH2, suggesting also a key role of frataxin in the mitochondrial electron transport chain in humans. Gonzalez-Cabo et al. (2005) suggested a direct participation of the respiratory chain in the pathogenesis of Friedreich ataxia, and proposed that it be considered as an OXPHOS disease.

Yfh1 interacts functionally and physically with Isu1 (ISCU; 611911), the scaffold protein on which the Fe/S clusters are assembled. Leidgens et al. (2010) generated 12 yeast Yfh1 mutants in conserved residues of the frataxin beta-sheet. The Q129A, I130A, W131A(F), and R141A mutations, which reside in surface-exposed residues of beta-strands, resulted in severe cell growth inhibition on high-iron media and low aconitase activity, indicating that Fe/S cluster biosynthesis was impaired. In contrast, gln129, trp131, and arg141 residues (which are spatially closely clustered) defined a patch important for protein function. Coimmunoprecipitation experiments showed that W131A, unlike W131F, was the sole mutation that strongly decreased the interaction with Isu1. Leidgens et al. (2010) concluded that trp131, which is the only strictly conserved frataxin residue in all sequenced species, appears essential for interaction with Isu1.

▼ Molecular Genetics

Mutation in the FXN gene has been shown to cause one form of Friedreich ataxia (229300). Most patients with Friedreich ataxia have a GAA-repeat expansion in the FXN gene. Delatycki et al. (1999) stated that 2% of cases of Friedreich ataxia are due to point mutations, the other 98% being due to expansion of a GAA trinucleotide repeat in intron 1. They indicated that 17 mutations had been described.

Campuzano et al. (1996) screened 184 patients with Friedreich ataxia for point mutations by PCR amplification of exons. Three different point mutations were found (606829.0002- 606829.0004). Seventy-nine unrelated FRDA patients, including 5 with point mutations, were screened for the GAA repeat expansion in the first intron (606829.0001). In the group of 74 patients without a point mutation, 71 were found to be homozygous for expanded alleles, and 3 were heterozygous for the expanded repeat. The 5 patients shown to carry point mutations were all found to be heterozygous for the repeat, and the repeat and the polymorphism had different parental origin. Repeat expansions in the patients were typically between 200 and 900 copies. In controls, the repeat expansion varied from 7 to 22 copies.

Delatycki et al. (1998) studied FRDA mutations in 66 Australian patients. One of 56 parents had a premutation with 1 normal allele and 1 allele of approximately 100 repeats in leukocyte DNA. His sperm showed an expanded allele in a tight range centering on a size of approximately 320 repeats. His affected son had repeat sizes of 1,040 and 540. Of 33 other father-to-offspring transmissions, 17 showed a definite decrease in allele size and 4 showed a decrease or no change; in 12 cases it was not possible to say if the allele had expanded or contracted in size. The authors stated that in all informative carrier father-to-affected child transmissions, other than in the premutation carrier, the expansion size decreased. Delatycki et al. (1998) concluded that expansion of the FRDA gene occurs in 2 stages, the first during meiosis followed by a second mitotic expansion.

Gacy et al. (1998) showed that the GAA instability in Friedreich ataxia is a DNA-directed mutation caused by improper DNA structure at the repeat region. Unlike CAG or CGG repeats, which form hairpins, GAA repeats form a YRY triple helix containing non-Watson-Crick pairs. As with hairpins, triplex mediates intergenerational instability in 96% of transmissions. In families with Friedreich ataxia, GAA instability is not a function of the number of long alleles, ruling out homologous recombination or gene conversion as a major mechanism. The similarity of mutation pattern among triple repeat-related diseases indicates that all trinucleotide instability occurs by a common, intraallelic mechanism that depends on DNA structure. Secondary structure mediates instability by creating strong polymerase pause sites at or within the repeats, facilitating slippage or sister chromatid exchange.

De Castro et al. (2000) analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. They found 7 compound heterozygous patients. In 4 patients, a point mutation that predicted a truncated frataxin was detected. Three of them were associated with classic early-onset Friedreich ataxia with an expanded GAA allele greater than 800 repeats. The fourth patient had disease onset at the late age of 29 years with a 350-GAA repeat expansion. In 2 patients manifesting the classic phenotype, no changes were observed by SSCP analysis. Linkage analysis in a family with 2 affected children with an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich patients are null mutations. In their collection of compound heterozygotes, clinical phenotypes seemed to be related to the GAA repeat number in the expanded allele.

To investigate the genetic background of apparently idiopathic sporadic cerebellar ataxia, Schols et al. (2000) tested for CAG/CTG trinucleotide repeats causing spinocerebellar ataxia types 1, 2 (SCA2; 183090), 3 (SCA3; 109150), 6 (SCA6; 183086), 7 (SCA7; 164500), 8 (SCA8; 608768), and 12 (SCA12; 604326), and the GAA repeat of the frataxin gene in 124 patients, including 20 patients with the clinical diagnosis of multiple system atrophy. Patients with a positive family history, atypical Friedreich phenotype, or symptomatic (secondary) ataxia were excluded. Genetic analyses uncovered the most common Friedreich mutation in 10 patients with an age of onset between 13 and 36 years. The SCA6 mutation was present in 9 patients with disease onset between 47 and 68 years of age. The CTG repeat associated with SCA8 was expanded in 3 patients. One patient had SCA2 attributable to a de novo mutation from a paternally transmitted, intermediate allele. Schols et al. (2000) did not identify the SCA1, SCA3, SCA7, or SCA12 mutations in this group of idiopathic sporadic ataxia patients. No trinucleotide repeat expansion was detected in the multiple system atrophy subgroup. This study revealed the genetic basis in 19% of apparently idiopathic ataxia patients. SCA6 was the most frequent mutation in late-onset cerebellar ataxia. The authors concluded that the frataxin trinucleotide expansion should be investigated in all sporadic ataxia patients with onset before age 40, even when the phenotype is atypical for Friedreich ataxia.

Sharma et al. (2002) used small-pool PCR to analyze somatic variability among 7,190 individual FRDA molecules from peripheral blood DNA of subjects carrying 12 different expanded alleles. Expanded alleles showed a length-dependent increase in somatic variability, with mutation loads ranging from 47 to 78%. There was a strong contraction bias among long alleles (more than 500 triplets), which showed a 4-fold higher frequency of large contractions versus expansions. Of all somatic mutations scored, 5% involved contractions of more than 50% of the original allele length, and 0.29% involved complete reversion to the normal/premutation length (60 triplets or fewer). These observations contrasted sharply with the strong expansion bias seen in CTG triplet repeats in myotonic dystrophy (DM1; 160900). No somatic variability was detected in more than 6000 individual FRDA molecules analyzed from 15 normal alleles (8 to 25 triplets). A premutation allele with 44 uninterrupted GAA repeats was found to be unstable, ranging in size from 6 to 113 triplets, thus establishing the threshold for somatic instability between 26 and 44 GAA triplets. The authors concluded that expanded GAA alleles in Friedreich ataxia are highly mutable and have a natural tendency to contract in vivo, and that these properties may depend on multiple factors, including DNA sequence, triplet-repeat length, and unknown cell type-specific factors.

Sharma et al. (2004) reported 2 unrelated patients with late-onset Friedreich ataxia who were compound heterozygous for a large clearly pathogenic GAA expansion and a smaller 'borderline' GAA expansion in the FXN gene. The first patient, who had expansions of 700 and 44 GAA repeats, developed ataxia symptoms in her early forties. The second patient, who had expansions of 915 and 66 GAA repeats, developed symptoms in his late twenties. Genomic analysis of several different tissues, including hair, skin, buccal cells, peripheral leukocytes, and fibroblasts, showed somatic instability of both the 44 and 66 repeat alleles. Cells from both patients showed an increase in mutation load, the proportion of individual FRDA molecules that differed in length from the constitutional allele by greater than 5%. Fifteen percent of the GAA-44 and 75% of the GAA-66 cells contained alleles with greater than 66 repeats. The 53-year-old asymptomatic brother of the first patient had alleles of 730 and 37 GAA repeats; the GAA-37 allele was somatically stable. Sharma et al. (2004) concluded that borderline expanded FRDA alleles ranging from 44 to 65 uninterrupted triplet repeats show somatic variability and may result in a disease phenotype if a large enough proportion of cells bear disease-causing expansions in pathologically affected tissues. Thus, persons who are compound heterozygous for a large repeat expansion and a borderline expansion have an increased risk of disease development.

In order to gain insight into GAA triplet repeat instability, Clark et al. (2004) analyzed all triplet repeats in the human genome. They determined that the GAA triplet repeat has a significant tendency to expand compared with all other triplet repeats. Eighty-nine percent of GAA repeats of 8 or more map to the G/A islands of Alu elements, and 58% map to Alu element poly(A) tails. Clark et al. (2004) found that only 2 other GAA repeats of 8 or more share the central Alu location seen at the FRDA locus. Clark et al. (2004) theorized that the GAA repeat coevolved with Alu elements during primate genomic evolution.

Pathogenic GAA repeat expansions in the FXN gene cause decreased mRNA expression of FXN by inhibiting transcription. In peripheral blood cells of 67 FRDA patients, Castaldo et al. (2008) used pyrosequencing to perform a quantitative analysis of the methylation status of 5 CpG sites located within intron 1 of the FXN gene, upstream of expanded GAA repeats. FRDA patients had increased methylation compared to controls. Significant differences were found for each CpG site tested, but the largest differences were found for CpG1 and CpG2 (84.45% and 76.80% methylation in patients compared to 19.65% and 23.34% in controls). There was a direct correlation between triplet expansion size and methylation at CpG1 and CpG2. In addition, a significant inverse correlation was observed between methylation at CpG1 and CpG2 and age of disease onset. Castaldo et al. (2008) concluded that epigenetic changes in the FXN gene may cause or contribute to gene silencing in FRDA.

▼ Genotype/Phenotype Correlations

Filla et al. (1996) studied the relationship between the trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. The length of the FA alleles ranged from 201 to 1,186 repeat units. There was no overlap between the size of normal alleles and the size of alleles found in FA. The lengths of both the larger and the smaller alleles varied inversely with the age of onset of the disorder. Filla et al. (1996) reported that the mean allele length was significantly higher in FA patients with diabetes and in those with cardiomyopathy. They noted that there was meiotic instability with a median variation of 150 repeats. Isnard et al. (1997) examined the correlation between the severity of left ventricular hypertrophy in Friedreich ataxia and the number of GAA repeats. Left ventricular wall thickness was measured in 44 patients using M-mode echocardiography and correlated with GAA expansion size on the smaller allele (267 to 1200 repeats). A significant correlation was found (r = 0.51, p less than 0.001), highlighting an important role for frataxin in the regulation of cardiac hypertrophy.

In a study of 187 patients with autosomal recessive ataxia, Durr et al. (1996) found that 140, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1,700 repeats of the trinucleotides. About one-quarter of the patients, despite being homozygous, had atypical Friedreich ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair of alleles) was associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs. The GAA repeats were unstable during transmission. Thus, the clinical spectrum of Friedreich ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion is useful for the diagnosis, prognosis, and genetic counseling.

Pianese et al. (1997) presented data suggesting that (1) the FRDA GAA repeat is highly unstable during meiosis, (2) contractions outnumber expansions, (3) both parental source and sequence length are important factors in variability of FRDA expanded alleles, and (4) the tendency to contract or expand does not seem to be associated with particular haplotypes. Thus, they concluded that FRDA gene variability appears to be different from that found with other triplet diseases.

Bidichandani et al. (1997) found an atypical FRDA phenotype associated with a remarkably slow rate of disease progression in a Caucasian family. It was caused by compound heterozygosity for a G130V missense mutation (606829.0005) and the GAA expansion of the X25 gene. The missense mutation G130V was the second mutation to be identified in the X25 gene and the first to be associated with a variant FRDA phenotype. This and the other reported missense mutation (I154F; 229300.0004) mapped within the highly conserved sequence domain in the C terminus of the frataxin gene. Since the G130V mutation was unlikely to affect the ability of the first 16 exons of the neighboring STM7 gene to encode a functional phosphatidylinositol phosphate kinase, Bidichandani et al. (1997) questioned the role of STM7 in Friedreich ataxia.

Since Friedreich ataxia is an autosomal recessive disease, it does not show typical features observed in other dynamic mutation disorders, such as anticipation. Monros et al. (1997) analyzed the GAA repeat in 104 FA patients and 163 carrier relatives previously defined by linkage analysis. The GAA expansion was detected in all patients, most (94%) of them being homozygous for the mutation. They demonstrated that clinical variability in FA is related to the size of the expanded repeat: milder forms of the disease (late-onset FA and FA with retained reflexes) were associated with shorter expansions, especially with the smaller of the 2 expanded alleles. Absence of cardiomyopathy was also associated with shorter alleles. Dynamics of the GAA repeat were investigated in 212 parent-offspring pairs. Meiotic instability showed a sex bias: paternally transmitted alleles tended to decrease in a linear way that depended on the paternal expansion size, whereas maternal alleles either increased or decreased in size. All but 1 of the patients with late-onset FA were homozygous for the GAA expansion; the exceptional individual was heterozygous for the expansion and for another unknown mutation. All but 1 of the FA patients with retained reflexes exhibited an axonal sensory neuropathy. However, preservation of their tendon reflexes suggested that the physiologic pathways of the reflex arch remained functional. A close relationship was found between late-onset disease and absence of heart muscle disease.

Delatycki et al. (1999) studied FRDA1 mutations in FA patients from Eastern Australia. Of the 83 people studied, 78 were homozygous for an expanded GAA repeat, while the other 5 had an expansion in one allele and a point mutation in the other. The authors presented a detailed study of 51 patients homozygous for an expanded GAA repeat. They identified an association between the size of the smaller of the 2 expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. However, no significant association was identified between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size was associated with bladder symptoms and the presence of foot deformity.

Gellera et al. (2007) reported 13 FA patients from 12 unrelated Italian families who were compound heterozygous for the GAA expansion and a small mutation in the FXN gene. Two missense and 5 frameshift or truncating mutations were identified (see, e.g., 606829.0007; 606829.0008). In all 13 patients, there was a significant inverse correlation between GAA size and age at onset. In 6 patients, age at onset correlated with residual protein level, and GAA size inversely correlated with residual protein level. Clinical data were consistent with the hypothesis that FXN mutations are more severe than GAA expansions. In patients with a null mutation and the GAA expansion, age at onset was strongly dependent on the size of the expansion, indicating that residual protein function derived from the expanded allele.

▼ History

Duclos et al. (1993) identified a transcript containing the conserved sequences around the D9S5 locus. The 7-kb transcript corresponded to a gene designated X11 (APBA1; 602414) which extended at least 80 kb in a direction opposite D9S15. The gene was expressed in the brain, including the cerebellum, but was not detectable in several nonneuronal tissues and cell lines. In situ hybridization of adult mouse brain sections showed prominent expression in the granular layer of the cerebellum. Expression was also found in the spinal cord. The cDNA contained an open reading frame encoding a 708-amino acid sequence that showed no significant similarity to other known proteins but contained a unique, 24-residue, putative transmembrane segment. On the basis of these findings, Duclos et al. (1993) suggested that this 'pioneer' gene represents the FRDA gene. Further studies by Rodius et al. (1994) excluded X11 as a candidate for the Friedreich ataxia gene.

Carvajal et al. (1995) reported the isolation of a gene from the FRDA critical region. Although no evidence of mutation was detected in the transcript, the sequence, which they designated STM7 (602745), represented only one of the shorter alternatively spliced species identified by Northern analysis and direct sequencing. Carvajal et al. (1995) still considered the gene a strong candidate for FRDA. Carvajal et al. (1996) reported that the X25 gene (frataxin-encoding gene) described by Campuzano et al. (1996) comprises part of STM7. They reported that the transcription of both STM7 and X25 occurs from the centromere toward the telomere, that the reported sequences of STM7 and X25 did not represent a full-length transcript, that multiple transcripts for each of these genes are present in Northern blots, and that several of these transcripts are of similar size. Carvajal et al. (1996) also reported that less than 10 kb separates the CpG island identified in the X25/exon 1 from the 3-prime end of STM7/exon 16. They further demonstrated that the recombinant protein corresponding to the STM7.1 transcript has phosphatidylinositol-4-phosphate 5-kinase activity. They noted that the ataxia-telangiectasia gene (607585) has C-terminal similarity to the catalytic domains of phosphatidylinositol phosphate 3-kinases. This homology, and the observation by Matsumoto et al. (1996) of an ataxia phenotype in mice lacking the type 1 inositol-1,4,5-triphosphate receptor (147265), provided support for a defect in the phosphoinositide pathway constituting the pathogenetic basis of Friedreich ataxia.

Cossee et al. (1997) concluded that there was no strong argument for a role of STM7 in Friedreich ataxia, while the presence of mutations in the frataxin gene fulfilled all criteria required of the FRDA gene. In reply, Chamberlain et al. (1997) presented additional data and stated the opinion that 'Cossee et al. have failed to present either a plausible explanation for our original observations or a definitive argument to contradict our interpretation of the data.' In rebuttal, Pandolfo (1997) pointed out that no data have been presented showing the existence of STM7/frataxin transcripts with methods other than RT-PCR, the existence of a defect in PIP kinase activity in Friedreich patients, or the existence of disease-causing mutations in STM7. In a review article, Koenig and Mandel (1997) stated that there was strong evidence negating the claim that the frataxin exons are alternative 3-prime STM7 exons, namely, the structure of frataxin cDNAs and mouse intronless pseudogenes, the nature of point mutations found in some patients, and the size of the endogenous frataxin protein.

▼ Animal Model

Koutnikova et al. (1997) cloned the complete coding region of mouse frataxin and studied its pattern of expression in developing and adult tissues. They found by in situ hybridization analyses that mouse frataxin expression correlated well with the main site of neurodegeneration in Friedreich ataxia, but the expression pattern was broader than expected from the pathology of the disease. Frataxin mRNA was predominantly expressed in tissues with a high metabolic rate, including liver, kidney, brown fat, and heart. They showed that mouse and yeast frataxin homologs contain a potential mitochondrial targeting sequence in their N-terminal domains and that disruption of the yeast gene results in mitochondrial dysfunction.

Cossee et al. (2000) generated a mouse model of Friedreich ataxia by deletion of exon 4 of the Frda gene, leading to inactivation of the Frda gene product. Homozygous deletions caused embryonic lethality a few days after implantation; no iron accumulation was observed during embryonic resorption, suggesting that cell death may be due to a mechanism independent of iron accumulation. The authors suggested that the milder phenotype in humans may be due to residual frataxin expression associated with the expansion mutations.

Through a conditional gene targeting approach, Puccio et al. (2001) generated in parallel a striated muscle frataxin-deficient mouse line and a neuron/cardiac muscle frataxin-deficient line, which Seznec et al. (2004) showed that in frataxin-deficient mice, Fe-S enzyme deficiency occurred at 4 weeks of age, prior to cardiac dilatation and concomitant development of left ventricular hypertrophy, while mitochondrial iron accumulation occurred at a terminal stage. The antioxidant idebenone delayed the cardiac disease onset, progression and death of frataxin-deficient animals by 1 week, but did not correct the Fe-S enzyme deficiency. The authors concluded that frataxin is a necessary, albeit nonessential, component of the Fe-S cluster biogenesis, and that idebenone acts downstream of the primary Fe-S enzyme deficit.

Thierbach et al. (2005) disrupted expression of frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals had a reduced life span and developed multiple hepatic tumors. Livers also showed increased oxidative stress, impaired respiration, and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S)-containing proteins, which all led to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase (600289) was specifically impaired following disruption of frataxin. The authors hypothesized that frataxin may act as a mitochondrial tumor suppressor protein in mammals.

Schoenfeld et al. (2005) microarrayed murine frataxin-deficient heart tissue, liver tissue, and cardiocytes and observed a transcript downregulation to upregulation ratio of nearly 2:1 with a mitochondrial localization of transcriptional changes. Combining all mouse and human microarray data for frataxin-deficient cells and tissues, the most consistently decreased transcripts were mitochondrial coproporphyrinogen oxidase (CPOX; 121300) of the heme pathway and mature T-cell proliferation 1, a homolog of yeast COX23, which is thought to function as a mitochondrial metallochaperone. Quantitative RT-PCR studies confirmed the significant downregulation of Isu1 (ISCU; 611911), CPOX, and ferrochelatase at 10 weeks in mouse hearts. Mutant cells were resistant to aminolevulinate-dependent toxicity, and there was increased cellular protoporphyrin IX levels, reduced mitochondrial heme a and heme c levels, and reduced activity of cytochrome oxidase, suggesting a defect between protoporphyrin IX and heme a. Fe-chelatase activities were similar in mutants and controls, whereas Zn-chelatase activities were slightly elevated in mutants, supporting the idea of an altered metal-specificity of ferrochelatase. The authors suggested that frataxin deficiency may cause defects late in the heme pathway. Since ataxic symptoms occur in other diseases of heme deficiency, the authors suggested that the heme defect observed in frataxin-deficient cells could be primary to the pathophysiological process.

Anderson et al. (2005) used RNA interference (RNAi) to suppress the Drosophila frataxin homolog (Dfh) and observed. distinct phenotypes in larvae and adults, leading to giant long-lived larvae and to conditional short-lived adults. Drosophila frataxin silencing differentially dysregulated ferritin expression in adults but not in larvae, Silencing of Dfh in the peripheral nervous system, a specific focus of Friedreich pathology, permitted normal larval development but imposed a marked reduction in adult life span. In contrast, Dfh silencing in motor neurons had no deleterious effect in either larvae or adults. Finally, overexpression of Sod1 (147450), Sod2 (147460), or Cat (115500) did not suppress the failure of Dfh-deficient flies to successfully complete eclosion, suggesting a minimal role of oxidative stress in this phenotype.

Clark et al. (2007) found that transgenic mice carrying expanded human FXN GAA repeats (190 or 82 triplets) showed tissue-specific and age-dependent somatic instability specifically in the cerebellum and dorsal root ganglia. The GAA(190) allele showed some instability by 2 months and significant expansion by 12 months, slightly greater than that of GAA(82), suggesting that somatic instability was also repeat length-dependent. There were lower levels of repeat expansion in proliferating tissues, indicating that DNA replication per se was unlikely to be a major cause of age-dependent expansion.

Anderson et al. (2008) showed that ectopic expression of H2O2 scavengers suppressed the deleterious phenotypes associated with frataxin deficiency in a Drosophila model of FRDA. In contrast, augmentation with superoxide scavengers had no effect. Augmentation of endogenous catalase (CAT; 115500) restored the activity of reactive oxygen species-sensitive mitochondrial aconitase (ACO2; 100850) and enhanced resistance to H2O2 exposure, both of which were diminished by frataxin deficiency. Anderson et al. (2008) concluded that H2O2 is an important pathologic substrate underlying the phenotypes arising from frataxin deficiency in Drosophila.

Coppola et al. (2009) performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPARG; 601487) pathway is known to regulate both processes, the authors hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. They demonstrated a coordinate dysregulation of the PPARG coactivator Pgc1a (PPARGC1A; 604517) and transcription factor Srebp1 (SREBF1; 184756) in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Genetic modulation of the PPAR-gamma pathway affected frataxin levels in vitro, supporting PPAR-gamma as a potential therapeutic target in FRDA.

▼ ALLELIC VARIANTS ( 9 Selected Examples):

Table View ClinVar

.0001 FRIEDREICH ATAXIA

FRIEDREICH ATAXIA WITH RETAINED REFLEXES, INCLUDED

FXN, (GAA)n REPEAT EXPANSION, IVS1

RCV000004184...

GAA triplet repeat expansions between 200 and 900 copies in the first intron of the frataxin gene occurred in 71 of 74 FRDA (229300) patients studied by Campuzano et al. (1996). In unaffected individuals, the triplet repeat expansion numbered between 7 and 20 units.

Among 101 FRDA patients homozygous for GAA expansion within the X25 gene, Coppola et al. (1999) found that 11 patients from 8 families had FRDA with retained reflexes in the lower limbs (FARR; see 229300). The mean size of the smaller allele was significantly less (408 +/- 252 vs 719 +/- 184 GAA triplets) in FARR patients.

.0002 FRIEDREICH ATAXIA

FXN, LEU106TER

RCV000004186

In 2 affected members of a French family with Friedreich ataxia (229300), Campuzano et al. (1996) identified compound heterozygosity for the FRDA expansion repeat (606829.0001) and a T-to-G transversion in exon 3 that changed a leucine (TTA) to a stop (TGA). The L106X mutation came from the father; the other allele carrying the expansion was from the mother.

.0003 FRIEDREICH ATAXIA

FXN, IVS3, A-G, -2

RCV000004187

Campuzano et al. (1996) found compound heterozygosity in a member of a Spanish family with Friedreich ataxia (229300) for the FRDA expansion repeat (606829.0001) and an A-to-G transition which disrupted the acceptor splice site at the end of the third intron.

.0004 FRIEDREICH ATAXIA

FXN, ILE154PHE

RCV000004188

Campuzano et al. (1996) studied 5 patients with Friedreich ataxia (229300) from 3 different Italian families and identified a change from isoleucine-154 to phenylalanine in exon 4. These patients were heterozygous for the FRDA expansion repeat (606829.0001). This I154F mutation was found to occur in 1 out of 417 chromosomes examined from the same Southern Italian population. Isoleucine at this position was highly conserved across species. (Koutnikova et al. (1998) referred to this mutation as ILE151PHE.)

Shan et al. (2007) showed that the I145F mutation did not affect FXN protein expression following transfection of HEK293T cells. However, I145F interfered with the interaction of FXN with ISD11 (LYRM4; 613311).

.0005 FRIEDREICH ATAXIA

FXN, GLY130VAL

RCV000004189...

Bidichandani et al. (1997) found compound heterozygosity for the GAA triplet-repeat expansion (606829.0001) and a novel missense mutation, G130V, in 3 sibs with variant Friedreich ataxia (229300). Three of 6 sibs were affected: a male age 42, a male age 39, and a female age 35. Onset of disease was in the early teens, starting with weakness in the lower limbs and followed by gradual progression over the ensuing 20 years. Two brothers were still ambulatory, using either a walking stick or walker, and led fully productive working lives. Their upper limbs were affected to a lesser extent than their legs and lacked several key signs. They had sensory loss over the distal limbs, mild to moderate motor weakness, impaired position and vibratory sense, and hypo- or areflexia. Bilateral Babinski sign was also present in 1 brother. There was no atrophy, and muscle tone was normal. Notably, there was no dysarthria, and coordination was either very mildly affected or normal. Nerve conduction studies revealed slowing of motor-conduction velocities and absent sensory-evoked responses. Magnetic resonance imaging (MRI) revealed cervical spinal cord atrophy. No cardiac abnormalities were detected. Blood glucose levels were borderline elevated, and mild glucose intolerance was revealed in a 5-hour glucose-tolerance test. The sister was somewhat more physically incapacitated than her older 2 brothers. (Koutnikova et al. (1998) referred to this mutation as GLY127VAL.)

By haplotype analysis in the 4 families that had been described with the G130V mutation, Delatycki et al. (1999) found results suggesting a common founder.

Using transfected HEK293T cells, Shan et al. (2007) showed that the G130V mutation interfered with FXN protein expression.

.0006 FRIEDREICH ATAXIA

FXN, MET1ILE

RCV000004190...

In 3 independent families, Zuhlke et al. (1998) found that affected individuals with Friedreich ataxia (229300) were compound heterozygotes for the repeat expansion (606829.0001) and an ATG-to-ATT (met1-to-ile; M1I) mutation of the start codon of the FXN gene. Haplotype analysis using 6 polymorphic chromosome 9 markers showed complete identity of haplotype in 2 of the 3 chromosomes with the point mutation; the third case showed partial conformity and may represent a single recombination event. A common ancestor was suspected. An M1I start codon mutation has been described in the HBB gene (141900.0430) as the cause of beta-0-thalassemia, in the OAT gene (258870.0001) as the cause of gyrate atrophy, in the PAH gene (261600.0048) as the cause of phenylketonuria, and in the PLP gene (312080.0015) as the cause of Pelizaeus-Merzbacher disease, but in all of these instances the nucleotide change represented an ATG-to-ATA transition.

.0007 FRIEDREICH ATAXIA

FXN, TRP173GLY

RCV000004191

In 2 unrelated patients with Friedreich ataxia (229300), Cossee et al. (1999) identified a TGG-to-GGG change in exon 5a of the FXN gene, resulting in a trp173-to-gly (W173G) substitution.

Gellera et al. (2007) identified a 517T-G transversion, resulting in a W173G substitution, in compound heterozygosity with the GAA expansion (606829.0001) in FA patients from 3 unrelated families of Italian origin. All patients had a severe form of the disorder with relatively early onset and presence of cardiomyopathy.

Using transfected HEK293T cells, Shan et al. (2007) showed that the W173G mutation interfered with FXN protein expression.

.0008 FRIEDREICH ATAXIA

FXN, 1-BP DEL, 157C

RCV000004192...

Gellera et al. (2007) identified a 1-bp deletion (157delC) in the FXN gene in compound heterozygosity with the GAA expansion (606829.0001) in patients with Friedreich ataxia (229300) from 4 unrelated families of Italian origin. The 1-bp deletion resulted in a frameshift and premature termination of the protein at codon 75. Three of the patients who had greater than 700 repeat expansions had onset by age 10 years. The fourth patient, with 170 repeats, had onset at age 32 years.

.0009 FRIEDREICH ATAXIA

FXN, 6-BP DEL/15-BP INS, NT371

RCV000029175

In 2 sibs with a rapidly progressive and severe Friedreich ataxia (229300), Evans-Galea et al. (2011) identified compound heterozygosity for a GAA expansion of 1,010 repeats in the FXN gene (606829.0001) and a deletion-insertion mutation in exon 3 (c.371_376del6ins15). The deletion-insertion mutation was predicted to change amino acid positions 124 through 127 from DVSF to VHLEDT, increasing frataxin from 211 to 214 residues. The mutant protein, if expressed, would have an altered acidic patch, impairing the interaction of FXN with iron and with the iron-sulphur cluster assembly factor. One sib had onset at age 4 years and was wheelchair-bound by age 8. The other had onset at age 5 years and was wheelchair-bound by age 10. Both had hypertrophic cardiomyopathy, dysarthria, kyphoscoliosis, decreased joint range, spasticity, and reduced hand function. Other features included diabetes mellitus and abnormal ocular function. One patient died at age 20 years.

▼ See Also:

Bidichandani et al. (1998); Gray and Johnson (1997); Montermini et al. (1997); Ohshima et al. (1998); Puccio and Koenig (2000); Sakamoto et al. (1999)

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Cossee, M., Campuzano, V., Koutnikova, H., Fischbeck, K., Mandel, J.-L., Koenig, M., Bidichandani, S. I., Patel, P. I., Molte, M. D., Canizares, J., De Frutos, R., Pianese, L., Cavalcanti, F., Monticelli, A., Cocozza, S., Montermini, L., Pandolfo, M. Frataxin fracas. (Letter) Nature Genet. 15: 337-338, 1997. [PubMed: 9090376, related citations] [Full Text]
Cossee, M., Durr, A., Schmitt, M., Dahl, N., Trouillas, P., Allinson, P., Kostrzewa, M., Nivelon-Chevallier, A., Gustavson, K.-H., Kohlschutter, A., Muller, U., Mandel, J.-L., and 11 others. Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. Ann. Neurol. 45: 200-206, 1999. [PubMed: 9989622, related citations] [Full Text]
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Karthikeyan, G., Santos, J. H., Graziewicz, M. A., Copeland, W. C., Isaya, G., Van Houten, B., Resnick, M. A. Reduction in frataxin causes progressive accumulation of mitochondrial damage. Hum. Molec. Genet. 12: 3331-3342, 2003. [PubMed: 14570713, related citations] [Full Text]
Koenig, M., Mandel, J.-L. Deciphering the cause of Friedreich ataxia. Curr. Opin. Neurobiol. 7: 689-694, 1997. [PubMed: 9384553, related citations] [Full Text]
Koutnikova, H., Campuzano, V., Foury, F., Dolle, P., Cazzalini, O., Koenig, M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nature Genet. 16: 345-351, 1997. [PubMed: 9241270, related citations] [Full Text]
Koutnikova, H., Campuzano, V., Koenig, M. Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase. Hum. Molec. Genet. 7: 1485-1489, 1998. [PubMed: 9700204, related citations] [Full Text]
Leidgens, S., De Smet, S., Foury, F. Frataxin interacts with Isu1 through a conserved tryptophan in its beta-sheet. Hum. Molec. Genet. 19: 276-286, 2010. [PubMed: 19884169, related citations] [Full Text]
Lesuisse, E., Santos, R., Matzanke, B. F., Knight, S. A. B., Camadro, J.-M., Dancis, A. Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1). Hum. Molec. Genet. 12: 879-889, 2003. [PubMed: 12668611, related citations] [Full Text]
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Contributors:

Bao Lige - updated : 12/11/2019

Cassandra L. Kniffin - updated : 7/16/2012
George E. Tiller - updated : 11/14/2011
George E. Tiller - updated : 12/29/2010
George E. Tiller - updated : 3/30/2010
Patricia A. Hartz - updated : 3/18/2010
Patricia A. Hartz - updated : 11/3/2009
George E. Tiller - updated : 9/3/2009
George E. Tiller - updated : 7/6/2009
George E. Tiller - updated : 11/19/2008
Patricia A. Hartz - updated : 8/21/2008
Patricia A. Hartz - updated : 3/4/2008
George E. Tiller - updated : 1/3/2008
Cassandra L. Kniffin - updated : 11/27/2007
George E. Tiller - updated : 5/21/2007
George E. Tiller - updated : 4/5/2007
George E. Tiller - updated : 1/10/2006
George E. Tiller - updated : 5/23/2005
Cassandra L. Kniffin - updated : 4/29/2005
George E. Tiller - updated : 2/21/2005
Ada Hamosh - updated : 8/25/2004
Patricia A. Hartz - updated : 3/11/2004
George E. Tiller - updated : 9/23/2003
George E. Tiller - updated : 7/10/2003
George E. Tiller - updated : 7/8/2003
George E. Tiller - updated : 2/24/2003
George E. Tiller - updated : 10/29/2002
George E. Tiller - updated : 9/18/2002

Creation Date:

Cassandra L. Kniffin : 4/4/2002

Edit History:

mgross : 12/11/2019

carol : 11/01/2019
alopez : 10/09/2019
alopez : 09/23/2016
carol : 09/20/2013
carol : 9/16/2013
terry : 9/14/2012
alopez : 7/18/2012
ckniffin : 7/16/2012
carol : 11/15/2011
terry : 11/14/2011
wwang : 1/11/2011
terry : 12/29/2010
wwang : 4/2/2010
terry : 3/30/2010
mgross : 3/18/2010
mgross : 3/18/2010
terry : 3/18/2010
wwang : 1/21/2010
mgross : 11/10/2009
terry : 11/3/2009
wwang : 9/17/2009
alopez : 9/16/2009
wwang : 9/10/2009
terry : 9/3/2009
alopez : 7/8/2009
terry : 7/6/2009
wwang : 4/6/2009
ckniffin : 2/11/2009
wwang : 11/19/2008
carol : 11/6/2008
mgross : 8/22/2008
terry : 8/21/2008
mgross : 3/4/2008
ckniffin : 3/4/2008
wwang : 1/9/2008
terry : 1/3/2008
wwang : 12/4/2007
ckniffin : 11/27/2007
wwang : 6/1/2007
terry : 5/21/2007
alopez : 4/13/2007
terry : 4/5/2007
wwang : 11/28/2006
ckniffin : 10/31/2006
wwang : 1/30/2006
terry : 1/10/2006
tkritzer : 5/23/2005
wwang : 5/18/2005
wwang : 5/13/2005
ckniffin : 4/29/2005
wwang : 3/9/2005
terry : 2/21/2005
tkritzer : 8/25/2004
terry : 8/25/2004
carol : 7/2/2004
mgross : 3/11/2004
mgross : 3/11/2004
terry : 3/11/2004
cwells : 9/23/2003
cwells : 7/10/2003
cwells : 7/8/2003
ckniffin : 3/11/2003
cwells : 2/24/2003
cwells : 10/29/2002
cwells : 9/18/2002
carol : 4/26/2002
ckniffin : 4/24/2002
ckniffin : 4/24/2002

* 606829

FRATAXIN; FXN

Alternative titles; symbols

FRDA GENE
X25

HGNC Approved Gene Symbol: FXN

SNOMEDCT: 10394003; ICD10CM: G11.11; ICD9CM: 334.0;

Cytogenetic location: 9q21.11 Genomic coordinates (GRCh38): 9:69,035,752-69,079,076 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
9q21.11	Friedreich ataxia	229300	Autosomal recessive	3
9q21.11	Friedreich ataxia with retained reflexes	229300	Autosomal recessive	3

TEXT

Description

Cloning and Expression

Gene Structure

Campuzano et al. (1996) found that the FXN gene contains 6 exons.

Mapping

By sequence analysis, Campuzano et al. (1996) mapped the FXN gene to chromosome 9q13.

Gene Function

Studies Using the Yeast Frataxin Homolog

Molecular Genetics

Genotype/Phenotype Correlations

History

Animal Model

ALLELIC VARIANTS 9 Selected Examples):

.0001 FRIEDREICH ATAXIA

FRIEDREICH ATAXIA WITH RETAINED REFLEXES, INCLUDED

FXN, (GAA)n REPEAT EXPANSION, IVS1
ClinVar: RCV000004184, RCV000004185

.0002 FRIEDREICH ATAXIA

FXN, LEU106TER
SNP: rs104894105, gnomAD: rs104894105, ClinVar: RCV000004186

.0003 FRIEDREICH ATAXIA

FXN, IVS3, A-G, -2
SNP: rs140987490, ClinVar: RCV000004187

.0004 FRIEDREICH ATAXIA

FXN, ILE154PHE
SNP: rs104894106, gnomAD: rs104894106, ClinVar: RCV000004188

.0005 FRIEDREICH ATAXIA

FXN, GLY130VAL
SNP: rs104894107, gnomAD: rs104894107, ClinVar: RCV000004189, RCV000992016

By haplotype analysis in the 4 families that had been described with the G130V mutation, Delatycki et al. (1999) found results suggesting a common founder.

Using transfected HEK293T cells, Shan et al. (2007) showed that the G130V mutation interfered with FXN protein expression.

.0006 FRIEDREICH ATAXIA

FXN, MET1ILE
SNP: rs104894108, gnomAD: rs104894108, ClinVar: RCV000004190, RCV001579769, RCV004017228

.0007 FRIEDREICH ATAXIA

FXN, TRP173GLY
SNP: rs56214919, ClinVar: RCV000004191

In 2 unrelated patients with Friedreich ataxia (229300), Cossee et al. (1999) identified a TGG-to-GGG change in exon 5a of the FXN gene, resulting in a trp173-to-gly (W173G) substitution.

Using transfected HEK293T cells, Shan et al. (2007) showed that the W173G mutation interfered with FXN protein expression.

.0008 FRIEDREICH ATAXIA

FXN, 1-BP DEL, 157C
SNP: rs141935559, ClinVar: RCV000004192, RCV001092266

.0009 FRIEDREICH ATAXIA

FXN, 6-BP DEL/15-BP INS, NT371
SNP: rs886037630, ClinVar: RCV000029175

REFERENCES

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Stehling, O., Elsasser, H.-P., Bruckel, B., Muhlenhoff, U., Lill, R. Iron-sulfur protein maturation in human cells: evidence for a function of frataxin. Hum. Molec. Genet. 13: 3007-3015, 2004. [PubMed: 15509595] [Full Text: https://doi.org/10.1093/hmg/ddh324]
Tan, G., Napoli, E., Taroni, F., Cortopassi, G. Decreased expression of genes involved in sulfur amino acid metabolism in frataxin-deficient cells. Hum. Molec. Genet. 12: 1699-1711, 2003. [PubMed: 12837693] [Full Text: https://doi.org/10.1093/hmg/ddg187]
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. H., Steinberg, P., Ristow, M. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Hum. Molec. Genet. 14: 3857-3864, 2005. Note: Erratum: Hum. Molec. Genet. 16: 2987 only, 2007. [PubMed: 16278235] [Full Text: https://doi.org/10.1093/hmg/ddi410]
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Contributors:

Bao Lige - updated : 12/11/2019
Cassandra L. Kniffin - updated : 7/16/2012
George E. Tiller - updated : 11/14/2011
George E. Tiller - updated : 12/29/2010
George E. Tiller - updated : 3/30/2010
Patricia A. Hartz - updated : 3/18/2010
Patricia A. Hartz - updated : 11/3/2009
George E. Tiller - updated : 9/3/2009
George E. Tiller - updated : 7/6/2009
George E. Tiller - updated : 11/19/2008
Patricia A. Hartz - updated : 8/21/2008
Patricia A. Hartz - updated : 3/4/2008
George E. Tiller - updated : 1/3/2008
Cassandra L. Kniffin - updated : 11/27/2007
George E. Tiller - updated : 5/21/2007
George E. Tiller - updated : 4/5/2007
George E. Tiller - updated : 1/10/2006
George E. Tiller - updated : 5/23/2005
Cassandra L. Kniffin - updated : 4/29/2005
George E. Tiller - updated : 2/21/2005
Ada Hamosh - updated : 8/25/2004
Patricia A. Hartz - updated : 3/11/2004
George E. Tiller - updated : 9/23/2003
George E. Tiller - updated : 7/10/2003
George E. Tiller - updated : 7/8/2003
George E. Tiller - updated : 2/24/2003
George E. Tiller - updated : 10/29/2002
George E. Tiller - updated : 9/18/2002

Creation Date:

Cassandra L. Kniffin : 4/4/2002

Edit History:

mgross : 12/11/2019
carol : 11/01/2019
alopez : 10/09/2019
alopez : 09/23/2016
carol : 09/20/2013
carol : 9/16/2013
terry : 9/14/2012
alopez : 7/18/2012
ckniffin : 7/16/2012
carol : 11/15/2011
terry : 11/14/2011
wwang : 1/11/2011
terry : 12/29/2010
wwang : 4/2/2010
terry : 3/30/2010
mgross : 3/18/2010
mgross : 3/18/2010
terry : 3/18/2010
wwang : 1/21/2010
mgross : 11/10/2009
terry : 11/3/2009
wwang : 9/17/2009
alopez : 9/16/2009
wwang : 9/10/2009
terry : 9/3/2009
alopez : 7/8/2009
terry : 7/6/2009
wwang : 4/6/2009
ckniffin : 2/11/2009
wwang : 11/19/2008
carol : 11/6/2008
mgross : 8/22/2008
terry : 8/21/2008
mgross : 3/4/2008
ckniffin : 3/4/2008
wwang : 1/9/2008
terry : 1/3/2008
wwang : 12/4/2007
ckniffin : 11/27/2007
wwang : 6/1/2007
terry : 5/21/2007
alopez : 4/13/2007
terry : 4/5/2007
wwang : 11/28/2006
ckniffin : 10/31/2006
wwang : 1/30/2006
terry : 1/10/2006
tkritzer : 5/23/2005
wwang : 5/18/2005
wwang : 5/13/2005
ckniffin : 4/29/2005
wwang : 3/9/2005
terry : 2/21/2005
tkritzer : 8/25/2004
terry : 8/25/2004
carol : 7/2/2004
mgross : 3/11/2004
mgross : 3/11/2004
terry : 3/11/2004
cwells : 9/23/2003
cwells : 7/10/2003
cwells : 7/8/2003
ckniffin : 3/11/2003
cwells : 2/24/2003
cwells : 10/29/2002
cwells : 9/18/2002
carol : 4/26/2002
ckniffin : 4/24/2002
ckniffin : 4/24/2002

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OMIM^® and Online Mendelian Inheritance in Man^® are registered trademarks of the Johns Hopkins University.
Copyright^® 1966-2024 Johns Hopkins University.
Printed: April 24, 2024

▼ External Links

FRATAXIN; FXN

FRDA GENE X25

TEXT

▼ Description

▼ Cloning and Expression

▼ Gene Structure

▼ Mapping

▼ Gene Function

▼ Molecular Genetics

▼ Genotype/Phenotype Correlations

▼ History

▼ Animal Model

▼ ALLELIC VARIANTS ( 9 Selected Examples):

.0001 FRIEDREICH ATAXIA

.0002 FRIEDREICH ATAXIA

.0003 FRIEDREICH ATAXIA

.0004 FRIEDREICH ATAXIA

.0005 FRIEDREICH ATAXIA

.0006 FRIEDREICH ATAXIA

.0007 FRIEDREICH ATAXIA

.0008 FRIEDREICH ATAXIA

.0009 FRIEDREICH ATAXIA

▼ See Also:

▼ REFERENCES

* 606829

FRATAXIN; FXN

FRDA GENE X25

Gene-Phenotype Relationships

TEXT

Description

Cloning and Expression

Gene Structure

Mapping

Gene Function

Molecular Genetics

Genotype/Phenotype Correlations

History

Animal Model

ALLELIC VARIANTS 9 Selected Examples):

.0001 FRIEDREICH ATAXIA

.0002 FRIEDREICH ATAXIA

.0003 FRIEDREICH ATAXIA

.0004 FRIEDREICH ATAXIA

.0005 FRIEDREICH ATAXIA

.0006 FRIEDREICH ATAXIA

.0007 FRIEDREICH ATAXIA

.0008 FRIEDREICH ATAXIA

.0009 FRIEDREICH ATAXIA

See Also:

REFERENCES

▼

External Links

FRDA GENE
X25

FRDA GENE
X25