“Frataxin”的意思、由来-开放百科全书

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.).^[4]^[5]^[6]

Clinical significance

Reduced expression of frataxin is the cause of Friedreich's ataxia (FRDA), a 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^[7] or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in bacteria^[8] and Human cells^[9] or both. The expansion of intronic trinucleotide repeat GAA results in Friedreich's ataxia.^[10] This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression.^[11]

96% of FRDA patients have a GAA trinucleotide repeat expansion in intron 1 of both alleles of their FXN gene.^[12] Overall, this leads to a decrease in frataxin mRNA synthesis and a decrease (but not absence) in frataxin protein in people with FRDA. (A subset of FRDA patients have GAA expansion in one chromosome and a point mutation in the FXN exon in the other chromosome.) In the typical case, the length of the allele with the shorter GAA expansion inversely correlates with frataxin levels. FRDA patients’ peripheral tissues typically have less than 10% of the frataxin levels exhibited by unaffected people.^[12] Lower levels of frataxin result in earlier disease onset and faster progression.

FRDA is characterized by ataxia, sensory loss, and cardiomyopathy. The reason frataxin deficiency causes these symptoms is not entirely clear. On a cellular level, it is linked to iron accumulation in the mitochondria and increased oxidant sensitivity. For reasons that are not well understood, this primarily affects the tissue of the dorsal root ganglia, cerebellum, and heart muscle.^[13]

Animal studies

An overexpression of frataxin in Drosophila has shown an increase in antioxidant capability, resistance to oxidative stress insults and longevity,^[14] supporting the theory that the role of frataxin is to protect the mitochondria from oxidative stress and the ensuing cellular damage.

Interactions

References

1. ^{{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 }}
2. ^{{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 }}
3. ^{{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 }}
4. ^{{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 }}
5. ^{{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 }}
6. ^{{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 }}
7. ^{{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 }}
8. ^{{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 }}
9. ^{{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 }}
10. ^{{cite web | title = Entrez Gene: FXN frataxin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2395| accessdate = }}
11. ^{{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 }}
12. ^¹{{cite journal |title=Role of frataxin protein deficiency and metabolic dysfunction in Friedreich ataxia, an autosomal recessive mitochondrial disease | vauthors=Clark E, Johnson J, Dong YN, Mercado-Ayon, Warren N, Zhai M, McMillan E, Salovin A, Lin H, Lynch DR |journal=Neuronal Signaling |date=Nov 2018 |doi=10.1042/NS20180060 |url=http://www.neuronalsignaling.org/content/2/4/NS20180060.full |accessdate=1 April 2019}}
13. ^{{cite journal | vauthors = Stemmler TL, Lesuisse E, Pain, Dancis |title=Frataxin and Mitochondrial FeS Cluster Biogenesis |journal=Journal of Biological Chemistry |date=August 2010 |doi= 10.1074/jbc.R110.118679 |url=http://www.jbc.org/content/285/35/26737.full |accessdate=25 March 2019}}
14. ^{{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 }}
15. ^¹²{{cite journal |vauthors=Khonsari H, Schneider M, Al-Mahdawi S, Chianea YG, Themis M, Parris C, Pook MA, Themis M |title=Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts |journal=Gene Ther. |volume=23 |issue=12 |pages=846–856 |date=December 2016 |pmid=27518705 |pmc=5143368 |doi=10.1038/gt.2016.61 |url=}}
16. ^{{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 }}

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 }}

{{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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 }}