Frataxin: Difference between revisions

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{{Redirect|FXN|the railway station|Foxton railway station}}
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{{Infobox_gene}}
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'''Frataxin''' is a [[protein]] that in humans is encoded by the FXN [[gene]].<ref name="pmid8596916">{{cite journal | vauthors = 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 | title = Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion | journal = Science | volume = 271 | issue = 5254 | pages = 1423–7 | date = Mar 1996 | pmid = 8596916 | doi = 10.1126/science.271.5254.1423 }}</ref><ref name="pmid8841185">{{cite journal | vauthors = Carvajal JJ, Pook MA, dos Santos M, Doudney K, Hillermann R, Minogue S, Williamson R, Hsuan JJ, Chamberlain S | title = The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase | journal = Nature Genetics | volume = 14 | issue = 2 | pages = 157–62 | date = Oct 1996 | pmid = 8841185 | doi = 10.1038/ng1096-157 }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_FXN_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1ekg.
| PDB = {{PDB2|1ekg}}, {{PDB2|1ly7}}
| Name = Frataxin
| HGNCid = 3951
| Symbol = FXN
| AltSymbols =; FA; CyaY; FARR; FRDA; MGC57199; X25
| OMIM = 606829
| ECnumber = 
| Homologene = 47908
| MGIid = 1096879
| GeneAtlas_image1 = PBB_GE_FXN_205565_s_at_tn.png
| Function = {{GNF_GO|id=GO:0004428 |text = inositol or phosphatidylinositol kinase activity}} {{GNF_GO|id=GO:0005381 |text = iron ion transmembrane transporter activity}} {{GNF_GO|id=GO:0009055 |text = electron carrier activity}}
| Component = {{GNF_GO|id=GO:0005739 |text = mitochondrion}}
| Process = {{GNF_GO|id=GO:0006118 |text = electron transport}} {{GNF_GO|id=GO:0006879 |text = cellular iron ion homeostasis}} {{GNF_GO|id=GO:0007268 |text = synaptic transmission}} {{GNF_GO|id=GO:0016192 |text = vesicle-mediated transport}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2395
    | Hs_Ensembl = ENSG00000165060
    | Hs_RefseqProtein = NP_000135
    | Hs_RefseqmRNA = NM_000144
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 9
    | Hs_GenLoc_start = 70839995
    | Hs_GenLoc_end = 70878949
    | Hs_Uniprot = Q16595
    | Mm_EntrezGene = 14297
    | Mm_Ensembl = ENSMUSG00000059363
    | Mm_RefseqmRNA = XM_989030
    | Mm_RefseqProtein = XP_994124
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 19
    | Mm_GenLoc_start = 24328550
    | Mm_GenLoc_end = 24347683
    | Mm_Uniprot = Q3TV21
  }}
}}


''Frataxin''' is a small [[protein]], localized to the [[mitochondrion]]. The function of frataxin is not entirely clear, but it seems to be involved in assembly of [[iron-sulfur cluster]]s.
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 cluster]]s. It has been proposed to act as either an iron [[Chaperone (protein)|chaperone]] or an iron storage protein.<ref name="pmid19305405">{{cite journal | vauthors = Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR, Bonomi F, Pastore A | title = Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS | journal = Nature Structural & Molecular Biology | volume = 16 | issue = 4 | pages = 390–6 | date = Apr 2009 | pmid = 19305405 | doi = 10.1038/nsmb.1579 }}</ref>


Deficiency of frataxin is the cause of [[Friedrich's ataxia]], a hereditary [[trinucleotide repeat disorder]].
Frataxin [[mRNA]] is predominantly [[gene expression|expressed]] in [[tissue (biology)|tissue]]s with a high [[metabolism|metabolic]] [[Rate (mathematics)|rate]] (including liver, kidney, brown fat and heart). [[Mus musculus|Mouse]] and [[Saccharomyces cerevisiae|yeast]] frataxin [[Homology (biology)|homologues]] contain a potential N-terminal [[mitochondrion|mitochondrial]] targeting sequence, and [[Homo sapiens|human]] frataxin has been observed to co-localise with a [[mitochondrial]] protein. Furthermore, disruption of the [[yeast]] gene has been shown to result in [[mitochondria]]l 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.).<ref name="pmid8596916">{{cite journal | vauthors = 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 | title = Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion | journal = Science | volume = 271 | issue = 5254 | pages = 1423–7 | date = Mar 1996 | pmid = 8596916 | doi = 10.1126/science.271.5254.1423 }}</ref><ref name="pmid8815938">{{cite journal | vauthors = Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M | title = Clinical and genetic abnormalities in patients with Friedreich's ataxia | journal = The New England Journal of Medicine | volume = 335 | issue = 16 | pages = 1169–75 | date = Oct 1996 | pmid = 8815938 | doi = 10.1056/NEJM199610173351601 }}</ref><ref name="pmid9241270">{{cite journal | vauthors = Koutnikova H, Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M | title = Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin | journal = Nature Genetics | volume = 16 | issue = 4 | pages = 345–51 | date = Aug 1997 | pmid = 9241270 | doi = 10.1038/ng0897-345 }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Clinical significance ==
{{PBB_Summary
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 modifications in the chromosomal entity<ref name="PMD21745819">{{cite journal | vauthors = Kim E, Napierala M, Dent SY | title = Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich's ataxia | journal = Nucleic Acids Research | volume = 39 | issue = 19 | pages = 8366–77 | date = Oct 2011 | pmid = 21745819 | pmc = 3201871 | doi = 10.1093/nar/gkr542 }}</ref> or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in Bacteria<ref name="PMD19733517">{{cite journal | vauthors = Pan X, Ding Y, Shi L | title = The roles of SbcCD and RNaseE in the transcription of GAA x TTC repeats in Escherichia coli | journal = DNA Repair | volume = 8 | issue = 11 | pages = 1321–7 | date = Nov 2009 | pmid = 19733517 | doi = 10.1016/j.dnarep.2009.08.001 }}</ref> and Human cells<ref name="PMD18597733">{{cite journal | vauthors = Baralle M, Pastor T, Bussani E, Pagani F | title = Influence of Friedreich ataxia GAA noncoding repeat expansions on pre-mRNA processing | journal = American Journal of Human Genetics | volume = 83 | issue = 1 | pages = 77–88 | date = Jul 2008 | pmid = 18597733 | pmc = 2443835 | doi = 10.1016/j.ajhg.2008.06.018 }}</ref> or both. The expansion of [[intron]]ic trinucleotide repeat GAA results in Friedreich's ataxia.<ref name="entrez">{{cite web | title = Entrez Gene: FXN frataxin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2395| accessdate = }}</ref> This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression.<ref>{{cite journal | vauthors = Li L, Matsui M, Corey DR | title = Activating frataxin expression by repeat-targeted nucleic acids | journal = Nature Communications | volume = 7 | pages = 10606 | date = 2016-01-01 | pmid = 26842135 | pmc = 4742999 | doi = 10.1038/ncomms10606 }}</ref>
| section_title =  
 
| summary_text = This nuclear gene encodes a mitochondrial protein which belongs to FRATAXIN family. The protein functions in regulating mitochondrial iron transport and respiration. The expansion of intronic trinucleotide repeat GAA results in Friedreich ataxia. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.<ref name="entrez">{{cite web | title = Entrez Gene: FXN frataxin| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2395| accessdate = }}</ref>
== Animal studies ==
}}
 
An overexpression of frataxin in ''[[Drosophila]]'' has shown an increase in antioxidant capability, resistance to oxidative stress insults and longevity.<ref name="pmid18258192">{{cite journal | vauthors = Runko AP, Griswold AJ, Min KT | title = Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila | journal = FEBS Letters | volume = 582 | issue = 5 | pages = 715–9 | date = Mar 2008 | pmid = 18258192 | doi = 10.1016/j.febslet.2008.01.046 }}</ref>
 
== Interactions ==
 
Frataxin has been shown to biologically [[Protein-protein interaction|interact]] with the enzyme [[PMPCB]].<ref name=pmid9700204>{{cite journal | vauthors = Koutnikova H, Campuzano V, Koenig M | title = Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase | journal = Human Molecular Genetics | volume = 7 | issue = 9 | pages = 1485–9 | date = Sep 1998 | pmid = 9700204 | doi = 10.1093/hmg/7.9.1485 }}</ref>
 
== References ==
{{reflist}}
 
== Further reading ==


==References==
{{reflist|2}}
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Thierbach R, Drewes G, Fusser M, Voigt A, Kuhlow D, Blume U, Schulz TJ, Reiche C, Glatt H, Epe B, Steinberg P, Ristow M | title = The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals | journal = The Biochemical Journal | volume = 432 | issue = 1 | pages = 165–72 | date = Nov 2010 | pmid = 20819074 | pmc = 2976068 | doi = 10.1042/BJ20101116 }}
| citations =
* {{cite journal | vauthors = Montermini L, Rodius F, Pianese L, Moltò MD, Cossée M, Campuzano V, Cavalcanti F, Monticelli A, Palau F, Gyapay G | title = The Friedreich ataxia critical region spans a 150-kb interval on chromosome 9q13 | journal = American Journal of Human Genetics | volume = 57 | issue = 5 | pages = 1061–7 | date = Nov 1995 | pmid = 7485155 | pmc = 1801369 | doi =  }}
*{{cite journal | author=Montermini L, Rodius F, Pianese L, ''et al.'' |title=The Friedreich ataxia critical region spans a 150-kb interval on chromosome 9q13. |journal=Am. J. Hum. Genet. |volume=57 |issue= 5 |pages= 1061-7 |year= 1995 |pmid= 7485155 |doi= }}
* {{cite journal | vauthors = Bidichandani SI, Ashizawa T, Patel PI | title = Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion | journal = American Journal of Human Genetics | volume = 60 | issue = 5 | pages = 1251–6 | date = May 1997 | pmid = 9150176 | pmc = 1712428 | doi =  }}
*{{cite journal | author=Campuzano V, Montermini L, Moltò MD, ''et al.'' |title=Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. |journal=Science |volume=271 |issue= 5254 |pages= 1423-7 |year= 1996 |pmid= 8596916 |doi=  }}
* {{cite journal | vauthors = Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, Pandolfo M, Kaplan J | title = Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin | journal = Science | volume = 276 | issue = 5319 | pages = 1709–12 | date = Jun 1997 | pmid = 9180083 | doi = 10.1126/science.276.5319.1709 }}
*{{cite journal | author=Carvajal JJ, Pook MA, dos Santos M, ''et al.'' |title=The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase. |journal=Nat. Genet. |volume=14 |issue= 2 |pages= 157-62 |year= 1996 |pmid= 8841185 |doi= 10.1038/ng1096-157 }}
* {{cite journal | vauthors = Koutnikova H, Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M | title = Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin | journal = Nature Genetics | volume = 16 | issue = 4 | pages = 345–51 | date = Aug 1997 | pmid = 9241270 | doi = 10.1038/ng0897-345 }}
*{{cite journal | author=Bidichandani SI, Ashizawa T, Patel PI |title=Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. |journal=Am. J. Hum. Genet. |volume=60 |issue= 5 |pages= 1251-6 |year= 1997 |pmid= 9150176 |doi= }}
* {{cite journal | vauthors = Wilson RB, Roof DM | title = Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue | journal = Nature Genetics | volume = 16 | issue = 4 | pages = 352–7 | date = Aug 1997 | pmid = 9241271 | doi = 10.1038/ng0897-352 }}
*{{cite journal | author=Babcock M, de Silva D, Oaks R, ''et al.'' |title=Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. |journal=Science |volume=276 |issue= 5319 |pages= 1709-12 |year= 1997 |pmid= 9180083 |doi= }}
* {{cite journal | vauthors = Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, Trottier Y, Kish SJ, Faucheux B, Trouillas P, Authier FJ, Dürr A, Mandel JL, Vescovi A, Pandolfo M, Koenig M | title = Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes | journal = Human Molecular Genetics | volume = 6 | issue = 11 | pages = 1771–80 | date = Oct 1997 | pmid = 9302253 | doi = 10.1093/hmg/6.11.1771 }}
*{{cite journal | author=Koutnikova H, Campuzano V, Foury F, ''et al.'' |title=Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. |journal=Nat. Genet. |volume=16 |issue= 4 |pages= 345-51 |year= 1997 |pmid= 9241270 |doi= 10.1038/ng0897-345 }}
* {{cite journal | vauthors = Rötig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P | title = Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia | journal = Nature Genetics | volume = 17 | issue = 2 | pages = 215–7 | date = Oct 1997 | pmid = 9326946 | doi = 10.1038/ng1097-215 }}
*{{cite journal | author=Wilson RB, Roof DM |title=Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. |journal=Nat. Genet. |volume=16 |issue= 4 |pages= 352-7 |year= 1997 |pmid= 9241271 |doi= 10.1038/ng0897-352 }}
* {{cite journal | vauthors = Jiralerspong S, Liu Y, Montermini L, Stifani S, Pandolfo M | title = Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo | journal = Neurobiology of Disease | volume = 4 | issue = 2 | pages = 103–13 | year = 1997 | pmid = 9331900 | doi = 10.1006/nbdi.1997.0139 }}
*{{cite journal | author=Campuzano V, Montermini L, Lutz Y, ''et al.'' |title=Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. |journal=Hum. Mol. Genet. |volume=6 |issue= 11 |pages= 1771-80 |year= 1998 |pmid= 9302253 |doi= }}
* {{cite journal | vauthors = Koutnikova H, Campuzano V, Koenig M | title = Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase | journal = Human Molecular Genetics | volume = 7 | issue = 9 | pages = 1485–9 | date = Sep 1998 | pmid = 9700204 | doi = 10.1093/hmg/7.9.1485 }}
*{{cite journal | author=Rötig A, de Lonlay P, Chretien D, ''et al.'' |title=Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. |journal=Nat. Genet. |volume=17 |issue= 2 |pages= 215-7 |year= 1997 |pmid= 9326946 |doi= 10.1038/ng1097-215 }}
* {{cite journal | vauthors = Zühlke C, Laccone F, Cossée M, Kohlschütter A, Koenig M, Schwinger E | title = Mutation of the start codon in the FRDA1 gene: linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor | journal = Human Genetics | volume = 103 | issue = 1 | pages = 102–5 | date = Jul 1998 | pmid = 9737785 | doi = 10.1007/s004390050791 }}
*{{cite journal | author=Jiralerspong S, Liu Y, Montermini L, ''et al.'' |title=Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. |journal=Neurobiol. Dis. |volume=4 |issue= 2 |pages= 103-13 |year= 1997 |pmid= 9331900 |doi= 10.1006/nbdi.1997.0139 }}
* {{cite journal | vauthors = Bartolo C, Mendell JR, Prior TW | title = Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies | journal = American Journal of Medical Genetics | volume = 79 | issue = 5 | pages = 396–9 | date = Oct 1998 | pmid = 9779809 | doi = 10.1002/(SICI)1096-8628(19981012)79:5<396::AID-AJMG13>3.0.CO;2-M }}
*{{cite journal | author=Koutnikova H, Campuzano V, Koenig M |title=Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase. |journal=Hum. Mol. Genet. |volume=7 |issue= 9 |pages= 1485-9 |year= 1998 |pmid= 9700204 |doi= }}
* {{cite journal | vauthors = Cossée M, Dürr A, Schmitt M, Dahl N, Trouillas P, Allinson P, Kostrzewa M, Nivelon-Chevallier A, Gustavson KH, Kohlschütter A, Müller U, Mandel JL, Brice A, Koenig M, Cavalcanti F, Tammaro A, De Michele G, Filla A, Cocozza S, Labuda M, Montermini L, Poirier J, Pandolfo M | title = Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes | journal = Annals of Neurology | volume = 45 | issue = 2 | pages = 200–6 | date = Feb 1999 | pmid = 9989622 | doi = 10.1002/1531-8249(199902)45:2<200::AID-ANA10>3.0.CO;2-U }}
*{{cite journal | author=Zühlke C, Laccone F, Cossée M, ''et al.'' |title=Mutation of the start codon in the FRDA1 gene: linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor. |journal=Hum. Genet. |volume=103 |issue= 1 |pages= 102-5 |year= 1998 |pmid= 9737785 |doi= }}
* {{cite journal | vauthors = Coppola G, De Michele G, Cavalcanti F, Pianese L, Perretti A, Santoro L, Vita G, Toscano A, Amboni M, Grimaldi G, Salvatore E, Caruso G, Filla A | title = Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study | journal = Journal of Neurology | volume = 246 | issue = 5 | pages = 353–7 | date = May 1999 | pmid = 10399865 | doi = 10.1007/s004150050362 }}
*{{cite journal  | author=Bartolo C, Mendell JR, Prior TW |title=Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies. |journal=Am. J. Med. Genet. |volume=79 |issue= 5 |pages= 396-9 |year= 1999 |pmid= 9779809 |doi= }}
* {{cite journal | vauthors = Branda SS, Cavadini P, Adamec J, Kalousek F, Taroni F, Isaya G | title = Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase | journal = The Journal of Biological Chemistry | volume = 274 | issue = 32 | pages = 22763–9 | date = Aug 1999 | pmid = 10428860 | doi = 10.1074/jbc.274.32.22763 }}
*{{cite journal  | author=Cossée M, Dürr A, Schmitt M, ''et al.'' |title=Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. |journal=Ann. Neurol. |volume=45 |issue= 2 |pages= 200-6 |year= 1999 |pmid= 9989622 |doi=  }}
* {{cite journal | vauthors = Gordon DM, Shi Q, Dancis A, Pain D | title = Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase | journal = Human Molecular Genetics | volume = 8 | issue = 12 | pages = 2255–62 | date = Nov 1999 | pmid = 10545606 | doi = 10.1093/hmg/8.12.2255 }}
*{{cite journal  | author=Coppola G, De Michele G, Cavalcanti F, ''et al.'' |title=Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study. |journal=J. Neurol. |volume=246 |issue= 5 |pages= 353-7 |year= 1999 |pmid= 10399865 |doi= }}
* {{cite journal | vauthors = Forrest SM, Knight M, Delatycki MB, Paris D, Williamson R, King J, Yeung L, Nassif N, Nicholson GA | title = The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene | journal = Neurogenetics | volume = 1 | issue = 4 | pages = 253–7 | date = Aug 1998 | pmid = 10732799 | doi = 10.1007/s100480050037 }}
*{{cite journal | author=Branda SS, Cavadini P, Adamec J, ''et al.'' |title=Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase. |journal=J. Biol. Chem. |volume=274 |issue= 32 |pages= 22763-9 |year= 1999 |pmid= 10428860 |doi= }}
* {{cite journal | vauthors = Al-Mahdawi S, Pook M, Chamberlain S | title = A novel missense mutation (L198R) in the Friedreich's ataxia gene | journal = Human Mutation | volume = 16 | issue = 1 | pages = 95 | date = Jul 2000 | pmid = 10874325 | doi = 10.1002/1098-1004(200007)16:1<95::AID-HUMU29>3.0.CO;2-E }}
*{{cite journal | author=Gordon DM, Shi Q, Dancis A, Pain D |title=Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase. |journal=Hum. Mol. Genet. |volume=8 |issue= 12 |pages= 2255-62 |year= 1999 |pmid= 10545606 |doi= }}
* {{cite journal | vauthors = Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE | title = Crystal structure of human frataxin | journal = The Journal of Biological Chemistry | volume = 275 | issue = 40 | pages = 30753–6 | date = Oct 2000 | pmid = 10900192 | doi = 10.1074/jbc.C000407200 }}
*{{cite journal | author=Forrest SM, Knight M, Delatycki MB, ''et al.'' |title=The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. |journal=Neurogenetics |volume=1 |issue= 4 |pages= 253-7 |year= 2000 |pmid= 10732799 |doi= }}
*{{cite journal | author=Al-Mahdawi S, Pook M, Chamberlain S |title=A novel missense mutation (L198R) in the Friedreich's ataxia gene. |journal=Hum. Mutat. |volume=16 |issue= 1 |pages= 95 |year= 2000 |pmid= 10874325 |doi= 10.1002/1098-1004(200007)16:1<95::AID-HUMU29>3.0.CO;2-E }}
*{{cite journal | author=Dhe-Paganon S, Shigeta R, Chi YI, ''et al.'' |title=Crystal structure of human frataxin. |journal=J. Biol. Chem. |volume=275 |issue= 40 |pages= 30753-6 |year= 2000 |pmid= 10900192 |doi= 10.1074/jbc.C000407200 }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1281/  GeneReviews/NCBI/NIH/UW entry on Friedreich Ataxia]
* {{MeshName|frataxin}}
* {{MeshName|frataxin}}


{{protein-stub}}
{{PDB Gallery|geneid=2395}}
[[Category:proteins]]
{{Mitochondrial enzymes}}
 
[[Category:Proteins]]

Revision as of 07:40, 31 August 2017

"FXN" redirects here. For the railway station, see Foxton railway station.
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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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RefSeq (protein)

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Wikidata
View/Edit Human

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

Function

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 modifications 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] This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression.[10]

Animal studies

An overexpression of frataxin in Drosophila has shown an increase in antioxidant capability, resistance to oxidative stress insults and longevity.[11]

Interactions

Frataxin has been shown to biologically interact with the enzyme PMPCB.[12]

References

  1. ↑ 1.0 1.1 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 (Mar 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.
  2. ↑ Carvajal JJ, Pook MA, dos Santos M, Doudney K, Hillermann R, Minogue S, Williamson R, Hsuan JJ, Chamberlain S (Oct 1996). "The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase". Nature Genetics. 14 (2): 157–62. doi:10.1038/ng1096-157. PMID 8841185.
  3. ↑ Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR, Bonomi F, Pastore A (Apr 2009). "Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS". Nature Structural & Molecular Biology. 16 (4): 390–6. doi:10.1038/nsmb.1579. PMID 19305405.
  4. ↑ Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (Oct 1996). "Clinical and genetic abnormalities in patients with Friedreich's ataxia". The New England Journal of Medicine. 335 (16): 1169–75. doi:10.1056/NEJM199610173351601. PMID 8815938.
  5. ↑ Koutnikova H, Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M (Aug 1997). "Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin". Nature Genetics. 16 (4): 345–51. doi:10.1038/ng0897-345. PMID 9241270.
  6. ↑ Kim E, Napierala M, Dent SY (Oct 2011). "Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich's ataxia". Nucleic Acids Research. 39 (19): 8366–77. doi:10.1093/nar/gkr542. PMC 3201871. PMID 21745819.
  7. ↑ Pan X, Ding Y, Shi L (Nov 2009). "The roles of SbcCD and RNaseE in the transcription of GAA x TTC repeats in Escherichia coli". DNA Repair. 8 (11): 1321–7. doi:10.1016/j.dnarep.2009.08.001. PMID 19733517.
  8. ↑ Baralle M, Pastor T, Bussani E, Pagani F (Jul 2008). "Influence of Friedreich ataxia GAA noncoding repeat expansions on pre-mRNA processing". American Journal of Human Genetics. 83 (1): 77–88. doi:10.1016/j.ajhg.2008.06.018. PMC 2443835. PMID 18597733.
  9. ↑ "Entrez Gene: FXN frataxin".
  10. ↑ Li L, Matsui M, Corey DR (2016-01-01). "Activating frataxin expression by repeat-targeted nucleic acids". Nature Communications. 7: 10606. doi:10.1038/ncomms10606. PMC 4742999. PMID 26842135.
  11. ↑ Runko AP, Griswold AJ, Min KT (Mar 2008). "Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila". FEBS Letters. 582 (5): 715–9. doi:10.1016/j.febslet.2008.01.046. PMID 18258192.
  12. ↑ Koutnikova H, Campuzano V, Koenig M (Sep 1998). "Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase". Human Molecular Genetics. 7 (9): 1485–9. doi:10.1093/hmg/7.9.1485. PMID 9700204.

Further reading

  • Thierbach R, Drewes G, Fusser M, Voigt A, Kuhlow D, Blume U, Schulz TJ, Reiche C, Glatt H, Epe B, Steinberg P, Ristow M (Nov 2010). "The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals". The Biochemical Journal. 432 (1): 165–72. doi:10.1042/BJ20101116. PMC 2976068. PMID 20819074.
  • Montermini L, Rodius F, Pianese L, Moltò MD, Cossée M, Campuzano V, Cavalcanti F, Monticelli A, Palau F, Gyapay G (Nov 1995). "The Friedreich ataxia critical region spans a 150-kb interval on chromosome 9q13". American Journal of Human Genetics. 57 (5): 1061–7. PMC 1801369. PMID 7485155.
  • Bidichandani SI, Ashizawa T, Patel PI (May 1997). "Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion". American Journal of Human Genetics. 60 (5): 1251–6. PMC 1712428. PMID 9150176.
  • Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, Pandolfo M, Kaplan J (Jun 1997). "Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin". Science. 276 (5319): 1709–12. doi:10.1126/science.276.5319.1709. PMID 9180083.
  • Koutnikova H, Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M (Aug 1997). "Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin". Nature Genetics. 16 (4): 345–51. doi:10.1038/ng0897-345. PMID 9241270.
  • Wilson RB, Roof DM (Aug 1997). "Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue". Nature Genetics. 16 (4): 352–7. doi:10.1038/ng0897-352. PMID 9241271.
  • Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, Trottier Y, Kish SJ, Faucheux B, Trouillas P, Authier FJ, Dürr A, Mandel JL, Vescovi A, Pandolfo M, Koenig M (Oct 1997). "Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes". Human Molecular Genetics. 6 (11): 1771–80. doi:10.1093/hmg/6.11.1771. PMID 9302253.
  • Rötig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P (Oct 1997). "Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia". Nature Genetics. 17 (2): 215–7. doi:10.1038/ng1097-215. PMID 9326946.
  • Jiralerspong S, Liu Y, Montermini L, Stifani S, Pandolfo M (1997). "Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo". Neurobiology of Disease. 4 (2): 103–13. doi:10.1006/nbdi.1997.0139. PMID 9331900.
  • Koutnikova H, Campuzano V, Koenig M (Sep 1998). "Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase". Human Molecular Genetics. 7 (9): 1485–9. doi:10.1093/hmg/7.9.1485. PMID 9700204.
  • Zühlke C, Laccone F, Cossée M, Kohlschütter A, Koenig M, Schwinger E (Jul 1998). "Mutation of the start codon in the FRDA1 gene: linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor". Human Genetics. 103 (1): 102–5. doi:10.1007/s004390050791. PMID 9737785.
  • Bartolo C, Mendell JR, Prior TW (Oct 1998). "Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies". American Journal of Medical Genetics. 79 (5): 396–9. doi:10.1002/(SICI)1096-8628(19981012)79:5<396::AID-AJMG13>3.0.CO;2-M. PMID 9779809.
  • Cossée M, Dürr A, Schmitt M, Dahl N, Trouillas P, Allinson P, Kostrzewa M, Nivelon-Chevallier A, Gustavson KH, Kohlschütter A, Müller U, Mandel JL, Brice A, Koenig M, Cavalcanti F, Tammaro A, De Michele G, Filla A, Cocozza S, Labuda M, Montermini L, Poirier J, Pandolfo M (Feb 1999). "Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes". Annals of Neurology. 45 (2): 200–6. doi:10.1002/1531-8249(199902)45:2<200::AID-ANA10>3.0.CO;2-U. PMID 9989622.
  • Coppola G, De Michele G, Cavalcanti F, Pianese L, Perretti A, Santoro L, Vita G, Toscano A, Amboni M, Grimaldi G, Salvatore E, Caruso G, Filla A (May 1999). "Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study". Journal of Neurology. 246 (5): 353–7. doi:10.1007/s004150050362. PMID 10399865.
  • Branda SS, Cavadini P, Adamec J, Kalousek F, Taroni F, Isaya G (Aug 1999). "Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase". The Journal of Biological Chemistry. 274 (32): 22763–9. doi:10.1074/jbc.274.32.22763. PMID 10428860.
  • Gordon DM, Shi Q, Dancis A, Pain D (Nov 1999). "Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase". Human Molecular Genetics. 8 (12): 2255–62. doi:10.1093/hmg/8.12.2255. PMID 10545606.
  • Forrest SM, Knight M, Delatycki MB, Paris D, Williamson R, King J, Yeung L, Nassif N, Nicholson GA (Aug 1998). "The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene". Neurogenetics. 1 (4): 253–7. doi:10.1007/s100480050037. PMID 10732799.
  • Al-Mahdawi S, Pook M, Chamberlain S (Jul 2000). "A novel missense mutation (L198R) in the Friedreich's ataxia gene". Human Mutation. 16 (1): 95. doi:10.1002/1098-1004(200007)16:1<95::AID-HUMU29>3.0.CO;2-E. PMID 10874325.
  • Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE (Oct 2000). "Crystal structure of human frataxin". The Journal of Biological Chemistry. 275 (40): 30753–6. doi:10.1074/jbc.C000407200. PMID 10900192.

External links

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