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Frataxin is a protein that in humans is encoded by the FXN gene.^[1]^[2]

Frataxin is localized to the mitochondrion. The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters. It has been proposed to act as either an iron chaperone or an iron storage protein.^[3]

Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin.).^[1]^[4]^[5]

Clinical significance

Reduced expression of frataxin is the cause of Friedreich's ataxia (FRDA), a lethal neurodegenerative disease. The reduction in frataxin gene expression may be attributable from either the silencing of transcription of the frataxin gene because of epigenetic modifciations in the chromosomal entity^[6] or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in Bacteria^[7] and Human cells^[8] or both. The expansion of intronic trinucleotide repeat GAA results in Friedreich's ataxia.^[9]

An overexpression of frataxin in Drosophila has shown an increase in antioxidant capability, resistance to oxidative stress insults and longevity.^[10]

Interactions

Frataxin has been shown to biologically interact with the enzyme PMPCB.^[11]

References

^ ^a ^b Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (March 1996). "Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion". Science 271 (5254): 1423–7. doi:10.1126/science.271.5254.1423. PMID 8596916.
^ Carvajal JJ, Pook MA, dos Santos M, Doudney K, Hillermann R, Minogue S, Williamson R, Hsuan JJ, Chamberlain S (October 1996). "The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase". Nat. Genet. 14 (2): 157–62. doi:10.1038/ng1096-157. PMID 8841185.
^ Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR, Bonomi F, Pastore A (April 2009). "Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS". Nat. Struct. Mol. Biol. 16 (4): 390–6. doi:10.1038/nsmb.1579. PMID 19305405.
^ Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (October 1996). "Clinical and genetic abnormalities in patients with Friedreich's ataxia". N. Engl. J. Med. 335 (16): 1169–75. doi:10.1056/NEJM199610173351601. PMID 8815938.
^ Koutnikova H, Campuzano V, Foury F, DollÃ© P, Cazzalini O, Koenig M (August 1997). "Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin". Nat. Genet. 16 (4): 345–51. doi:10.1038/ng0897-345. PMID 9241270.
^ Kim E, Napierala M, Dent SY (July 2011). "Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich's ataxia". Nucleic Acids Res. 39 (4): 1–12. doi:10.1093/nar/gkr542. PMC 3201871. PMID 21745819.
^ Pan X, Ding Y, Shi L (November 2009). "The roles of SbcCD and RNaseE in the transcription of GAA · TTC repeats in Escherichia coli". DNA Repair (Amst). 8 (11): 1321–7. doi:10.1016/j.dnarep.2009.08.001. PMID 19733517.
^ Baralle M, Pastor T, Bussani E, Pagani F (July 2008). "Influence of Friedreich Ataxia GAA Noncoding Repeat Expansions on Pre-mRNA Processing". Am J Hum Genet. 83 (1): 77–88. doi:10.1016/j.ajhg.2008.06.018. PMC 2443835. PMID 18597733.
^ "Entrez Gene: FXN frataxin".
^ Runko AP, Griswold AJ, Min KT (March 2008). "Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila". FEBS Lett. 582 (5): 715–9. doi:10.1016/j.febslet.2008.01.046. PMID 18258192.
^ Koutnikova, H; Campuzano V; Koenig M (Sep 1998). "Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase". Hum. Mol. Genet. (ENGLAND) 7 (9): 1485–9. doi:10.1093/hmg/7.9.1485. ISSN 0964-6906. PMID 9700204.

External links

GeneReviews/NCBI/NIH/UW entry on Friedreich Ataxia
frataxin at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. フリードライヒ失調症 friedreich ataxia
2. 心疾患関連する遺伝性症候群 inherited syndromes associated with cardiac disease
3. ハンチントン病：臨床的特徴および診断 huntington disease clinical features and diagnosis
4. 毛細血管拡張性運動失調症 ataxia telangiectasia

English Journal

Cardiac dysfunction exacerbated by endocrinopathies in friedreich ataxia: a case series.

Snyder M, Seyer L, Lynch DR, Resnick A, Zesiewicz TA.Source1Department of Neurology, University of South Florida College of Medicine, Parkinson's Disease and Movement, Disorders Center, Tampa, FL, USA.
Journal of child neurology.J Child Neurol.2012 Oct;27(10):1316-9. Epub 2012 Mar 8.
Friedreich ataxia is a neurodegenerative disease characterized by gait abnormalities, cardiomyopathy, and diabetes. Congestive heart failure was recently reported as the most frequent cause of Friedreich ataxia mortality. Cardiac dysfunction is suspected to result from a frataxin deficiency that lea
PMID 22408141

Relation of Cytosolic Iron Excess to Cardiomyopathy of Friedreich's Ataxia.

Ramirez RL, Qian J, Santambrogio P, Levi S, Koeppen AH.SourceVeterans Affairs Medical Center, Albany, New York.
The American journal of cardiology.Am J Cardiol.2012 Sep 20. pii: S0002-9149(12)01947-9. doi: 10.1016/j.amjcard.2012.08.018. [Epub ahead of print]
Cardiomyopathy is the leading cause of death in Friedreich's ataxia. This autosomal recessive disease is caused by a homozygous guanine-adenine-adenine trinucleotide repeat expansion in the frataxin gene (chromosome 9q21). One untoward effect of frataxin deficiency is the lack of iron (Fe)-sulfur cl
PMID 23000103

Japanese Journal

Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity

BULTEAU A. L.
Science 305, 242-245, 2004
NAID 30020391119

Zinc suppresses the iron-accumulation phenotype of Saccharomyces cerevisiae lacking the yeast frataxin homologue (Yfh1)

SANTOS R.
Biochem. J. 375, 247-254, 2003
NAID 80016220699

Cisplatin May Induce Frataxin Expression

Ghazizadeh Mohammad
Journal of Nippon Medical School 70(4), 367-371, 2003
… During cDNA microarray analyses of differential gene expression between a cisplatin-resistant A2780CP70 human ovarian carcinoma cell line and its parental A2780 cell line, we discovered that frataxin gene expression was frequently overexpressed in the cisplatin-resistant variant. … Decreased expression of frataxin protein is associated with Friedreich's ataxia (FRDA) which is a neurodegenerative disease involving ROS-mediated cellular damage. …
NAID 130004057244

Related Pictures

★リンクテーブル★

リンク元	「フリードライヒ運動失調症」「フラタキシン」

「フリードライヒ運動失調症」

Frataxin
	PDB rendering based on 1ekg.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1EKG, 1LY7, 3S4M, 3S5D, 3S5E, 3S5F, 3T3J, 3T3K, 3T3L, 3T3T, 3T3X
Identifiers
Symbols	FXN ; CyaY; FA; FARR; FRDA; X25
External IDs	OMIM: 606829 MGI: 1096879 HomoloGene: 47908 GeneCards: FXN Gene
EC number	1.16.3.1
Gene ontology
Molecular function	• ferroxidase activity; • protein binding; • ferrous iron binding; • ferric iron binding; • iron chaperone activity; • iron-sulfur cluster binding; • 2 iron, 2 sulfur cluster binding;
Cellular component	• mitochondrion; • mitochondrial matrix; • cytosol;
Biological process	• oxidative phosphorylation; • heme biosynthetic process; • ion transport; • cellular iron ion homeostasis; • mitochondrion organization; • adult walking behavior; • positive regulation of cell proliferation; • aerobic respiration; • embryo development ending in birth or egg hatching; • response to iron ion; • regulation of ferrochelatase activity; • protein autoprocessing; • iron incorporation into metallo-sulfur cluster; • proprioception; • positive regulation of cell growth; • negative regulation of multicellular organism growth; • negative regulation of apoptotic process; • small molecule metabolic process; • negative regulation of organ growth; • positive regulation of metalloenzyme activity; • positive regulation of lyase activity; • cellular response to hydrogen peroxide; • negative regulation of release of cytochrome c from mitochondria; • positive regulation of succinate dehydrogenase activity; • positive regulation of aconitate hydratase activity;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

英: Friedreich's ataxia Friedreich ataxia FA
同: フリードライヒ失調症, Friedreich運動失調症, Friedreich失調症,Friedreich病, フリードライヒ病 Friedreich disease、遺伝性脊髄性運動失調症 hereditary spinal ataxia
関: 脊髄小脳変性症

概念

脊髄小脳変性症の一型
主として病変が脊髄に限局された脊髄型

病因

FRDA(9q13)のfrataxin遺伝子におけるGAAリピートの増加あるいは点変異。

疫学

7-15歳発病が多い

遺伝形式

常染色体劣性遺伝 AR

病理

脊髄と小脳を中心とした変性

(1)脊髄後角、(2)脊髄小脳路、(3)錐体路の変性、(4)後根神経節、後根、末梢神経
後索、皮質脊髄路、脊髄小脳路に変性 (BET.335)

症状

下肢優位の後索症状、後根障害による反射消失

Babinski徴候、構音障害、知能障害、拡張型心筋症、足変形、脊柱側彎が高率に見られる。(BET.244)

初発症状:深部覚障害による失調性歩行。四肢末梢の筋萎縮、深部知覚障害(振動覚減弱)

慢性・進行性・左右対称性
運動失調は下肢から上肢に進展。運動失調は脊髄性に小脳性が加わってくる。

1. 脊髄後索・後脊髄小脳路・延髄の障害：　脊髄性失調

下肢の運動失調　→　足の変形　→　上肢の運動失調　→　失調性構音障害、眼振(YN.J-127)

2. 末梢神経障害：　後根の障害による。反射弓が障害されるので反射が消失する ex. 膝蓋腱反射の消失
3. 錐体路の障害：　原始反射出現。腱反射亢進
4. そのほか、心筋障害、糖尿病、知能低下、眼振、視神経萎縮、骨格の変形

検査

診断

治療

運動失調に対して、酒石酸プロチレリン(TRH)が唯一の治療薬(YN.J-127)

予後

緩徐に進行し20-25歳で運動不能(YN.J-127)

予防

参考

1.

http://www.nurs.or.jp/~academy/igaku/s7/s7431.htm

「フラタキシン」

　　[★]

英: frataxin
関: フリートライヒ運動失調症

see HIM 2570-2571 PON. 1053
フリートライヒ運動失調症と関連しているといわれている遺伝子で、9q13に座乗している。

[pmid8596916-1] Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (March 1996). "Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion". Science 271 (5254): 1423–7. doi:10.1126/science.271.5254.1423. PMID 8596916.

[pmid8841185-2] Carvajal JJ, Pook MA, dos Santos M, Doudney K, Hillermann R, Minogue S, Williamson R, Hsuan JJ, Chamberlain S (October 1996). "The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase". Nat. Genet. 14 (2): 157–62. doi:10.1038/ng1096-157. PMID 8841185.

[pmid19305405-3] Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR, Bonomi F, Pastore A (April 2009). "Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS". Nat. Struct. Mol. Biol. 16 (4): 390–6. doi:10.1038/nsmb.1579. PMID 19305405.

[pmid8815938-4] Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (October 1996). "Clinical and genetic abnormalities in patients with Friedreich's ataxia". N. Engl. J. Med. 335 (16): 1169–75. doi:10.1056/NEJM199610173351601. PMID 8815938.

[pmid9241270-5] Koutnikova H, Campuzano V, Foury F, DollÃ© P, Cazzalini O, Koenig M (August 1997). "Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin". Nat. Genet. 16 (4): 345–51. doi:10.1038/ng0897-345. PMID 9241270.

[PMD21745819-6] Kim E, Napierala M, Dent SY (July 2011). "Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich's ataxia". Nucleic Acids Res. 39 (4): 1–12. doi:10.1093/nar/gkr542. PMC 3201871. PMID 21745819.

[PMD19733517-7] Pan X, Ding Y, Shi L (November 2009). "The roles of SbcCD and RNaseE in the transcription of GAA · TTC repeats in Escherichia coli". DNA Repair (Amst). 8 (11): 1321–7. doi:10.1016/j.dnarep.2009.08.001. PMID 19733517.

[PMD18597733-8] Baralle M, Pastor T, Bussani E, Pagani F (July 2008). "Influence of Friedreich Ataxia GAA Noncoding Repeat Expansions on Pre-mRNA Processing". Am J Hum Genet. 83 (1): 77–88. doi:10.1016/j.ajhg.2008.06.018. PMC 2443835. PMID 18597733.

[entrez-9] "Entrez Gene: FXN frataxin".

[pmid18258192-10] Runko AP, Griswold AJ, Min KT (March 2008). "Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila". FEBS Lett. 582 (5): 715–9. doi:10.1016/j.febslet.2008.01.046. PMID 18258192.

[pmid9700204-11] Koutnikova, H; Campuzano V; Koenig M (Sep 1998). "Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase". Hum. Mol. Genet. (ENGLAND) 7 (9): 1485–9. doi:10.1093/hmg/7.9.1485. ISSN 0964-6906. PMID 9700204.

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案内

frataxin