フラタキシン
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出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2015/07/21 19:46:37」(JST)
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Frataxin |
PDB rendering based on 1ekg.
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Available structures |
PDB |
Ortholog search: PDBe, RCSB |
List of PDB id codes |
1EKG, 1LY7, 3S4M, 3S5D, 3S5E, 3S5F, 3T3J, 3T3K, 3T3L, 3T3T, 3T3X
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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
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Cellular component |
• mitochondrion
• mitochondrial matrix
• cytosol
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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
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Sources: Amigo / QuickGO |
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RNA expression pattern |
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More reference expression data |
Orthologs |
Species |
Human |
Mouse |
Entrez |
2395 |
14297 |
Ensembl |
ENSG00000165060 |
ENSMUSG00000059363 |
UniProt |
Q16595 |
O35943 |
RefSeq (mRNA) |
NM_000144 |
NM_008044 |
RefSeq (protein) |
NP_000135 |
NP_032070 |
Location (UCSC) |
Chr 9:
69.04 – 69.1 Mb |
Chr 19:
24.26 – 24.28 Mb |
PubMed search |
[1] |
[2] |
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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]
Contents
- 1 Clinical significance
- 2 Interactions
- 3 References
- 4 Further reading
- 5 External links
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, Dollé 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.
Further reading
- Thierbach, R.; Drewes, G.; Fusser, M.; Voigt, A.; Kuhlow, D.; Blume, U.; Schulz, T. J.; Reiche, C.; Glatt, H.; Epe, B.; Steinberg, P.; Ristow, M. (2010). "The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals". Biochemical Journal 432 (1): 165–172. doi:10.1042/BJ20101116. PMC 2976068. PMID 20819074. edit
- Montermini L, Rodius F, Pianese L et al. (1995). "The Friedreich Ataxia Critical Region Spans A 150-kb Interval on Chromosome 9q13". Am. J. Hum. Genet. 57 (5): 1061–7. PMC 1801369. PMID 7485155.
- Bidichandani SI, Ashizawa T, Patel PI (1997). "Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion". Am. J. Hum. Genet. 60 (5): 1251–6. PMC 1712428. PMID 9150176.
- Babcock M, de Silva D, Oaks R et al. (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 et al. (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.
- Wilson RB, Roof DM (1997). "Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue". Nat. Genet. 16 (4): 352–7. doi:10.1038/ng0897-352. PMID 9241271.
- Campuzano V, Montermini L, Lutz Y et al. (1998). "Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes". Hum. Mol. Genet. 6 (11): 1771–80. doi:10.1093/hmg/6.11.1771. PMID 9302253.
- Rötig A, de Lonlay P, Chretien D et al. (1997). "Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia". Nat. Genet. 17 (2): 215–7. doi:10.1038/ng1097-215. PMID 9326946.
- Jiralerspong S, Liu Y, Montermini L et al. (1997). "Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo". Neurobiol. Dis. 4 (2): 103–13. doi:10.1006/nbdi.1997.0139. PMID 9331900.
- Koutnikova H, Campuzano V, Koenig M (1998). "Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase". Hum. Mol. Genet. 7 (9): 1485–9. doi:10.1093/hmg/7.9.1485. PMID 9700204.
- Zühlke C, Laccone F, Cossée M et al. (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". Hum. Genet. 103 (1): 102–5. doi:10.1007/s004390050791. PMID 9737785.
- Bartolo C, Mendell JR, Prior TW (1999). "Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies". Am. J. Med. Genet. 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 et al. (1999). "Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes". Ann. Neurol. 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 et al. (1999). "Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study". J. Neurol. 246 (5): 353–7. doi:10.1007/s004150050362. PMID 10399865.
- Branda SS, Cavadini P, Adamec J et al. (1999). "Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase". J. Biol. Chem. 274 (32): 22763–9. doi:10.1074/jbc.274.32.22763. PMID 10428860.
- Gordon DM, Shi Q, Dancis A, Pain D (1999). "Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase". Hum. Mol. Genet. 8 (12): 2255–62. doi:10.1093/hmg/8.12.2255. PMID 10545606.
- Forrest SM, Knight M, Delatycki MB et al. (2000). "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 (2000). "A novel missense mutation (L198R) in the Friedreich's ataxia gene". Hum. Mutat. 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 et al. (2000). "Crystal structure of human frataxin". J. Biol. Chem. 275 (40): 30753–6. doi:10.1074/jbc.C000407200. PMID 10900192.
External links
- GeneReviews/NCBI/NIH/UW entry on Friedreich Ataxia
- frataxin at the US National Library of Medicine Medical Subject Headings (MeSH)
PDB gallery
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1ekg: MATURE HUMAN FRATAXIN
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1ly7: The solution structure of the c-terminal domain of frataxin, the protein responsible for friedreich ataxia
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Mitochondrial proteins
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Outer membrane |
fatty acid degradation |
- Carnitine palmitoyltransferase I
- Long-chain-fatty-acid—CoA ligase
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tryptophan metabolism |
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monoamine neurotransmitter
metabolism |
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Intermembrane space |
- Adenylate kinase
- Creatine kinase
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Inner membrane |
oxidative phosphorylation |
- Coenzyme Q – cytochrome c reductase
- Cytochrome c
- NADH dehydrogenase
- Succinate dehydrogenase
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pyrimidine metabolism |
- Dihydroorotate dehydrogenase
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mitochondrial shuttle |
- Malate-aspartate shuttle
- Glycerol phosphate shuttle
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other |
- Glutamate aspartate transporter
- Glycerol-3-phosphate dehydrogenase
- ATP synthase
- Carnitine palmitoyltransferase II
- Uncoupling protein
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Matrix |
citric acid cycle |
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- Oxoglutarate dehydrogenase complex
- Succinyl coenzyme A synthetase
- Fumarase
- Malate dehydrogenase
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anaplerotic reactions |
- Aspartate transaminase
- Glutamate dehydrogenase
- Pyruvate dehydrogenase complex
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urea cycle |
- Carbamoyl phosphate synthetase I
- Ornithine transcarbamylase
- N-Acetylglutamate synthase
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alcohol metabolism |
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Other/to be sorted |
steroidogenesis |
- Cholesterol side-chain cleavage enzyme
- Steroid 11-beta-hydroxylase
- Aldosterone synthase
- Frataxin
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- Mitochondrial membrane transport protein
- Mitochondrial permeability transition pore
- Mitochondrial carrier
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Mitochondrial DNA |
Complex I |
- MT-ND1
- MT-ND2
- MT-ND3
- MT-ND4
- MT-ND4L
- MT-ND5
- MT-ND6
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Complex III |
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Complex IV |
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ATP synthase |
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tRNA |
- MT-TA
- MT-TC
- MT-TD
- MT-TE
- MT-TF
- MT-TG
- MT-TH
- MT-TI
- MT-TK
- MT-TL1
- MT-TL2
- MT-TM
- MT-TN
- MT-TP
- MT-TQ
- MT-TR
- MT-TS1
- MT-TS2
- MT-TT
- MT-TV
- MT-TW
- MT-TY
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see also mitochondrial diseases
Index of cells
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Description |
- Structure
- Organelles
- peroxisome
- cytoskeleton
- centrosome
- epithelia
- cilia
- mitochondria
- Membranes
- Membrane transport
- ion channels
- vesicular transport
- solute carrier
- ABC transporters
- ATPase
- oxidoreduction-driven
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Disease |
- Structural
- peroxisome
- cytoskeleton
- cilia
- mitochondria
- nucleus
- scleroprotein
- Membrane
- channelopathy
- solute carrier
- ATPase
- ABC transporters
- other
- extracellular ligands
- cell surface receptors
- intracellular signalling
- Vesicular transport
- Pore-forming toxins
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UpToDate Contents
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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
- Zinc suppresses the iron-accumulation phenotype of Saccharomyces cerevisiae lacking the yeast frataxin homologue (Yfh1)
- 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 Links
- Citations of peer-reviewed research in which MitoSciences anti-frataxin monoclonal antibodies and/or immunoassays have been used: Chou C.J., Herman D., and Gottesfeld J.M. (2008). Pimelic diphenylamide 106 is a slow, tight ...
- Buy Frataxin antibodies from Santa Cruz. Select a Frataxin antibody from 1 monoclonal and 4 polyclonal antibodies. Frataxin si/shRNA products also available. ... HOVERcruz ,を紹介します。Frataxin Antibodiesを迅速に識別するため ...
Related Pictures
★リンクテーブル★
[★]
- 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
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
遺伝形式
病理
- (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。
- 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
予後
- 緩徐に進行し20-25歳で運動不能(YN.J-127)
予防
参考
- http://www.nurs.or.jp/~academy/igaku/s7/s7431.htm
[★]
- 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。