Description: Homo sapiens frataxin (FXN), nuclear gene encoding mitochondrial protein, transcript variant 1, mRNA. RefSeq Summary (NM_000144): This nuclear gene encodes a mitochondrial protein which belongs to the FRATAXIN family. The protein functions in regulating mitochondrial iron transport and respiration. The expansion of intronic trinucleotide repeat GAA from 8-33 repeats to >90 repeats results in Friedreich ataxia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]. Transcript (Including UTRs) Position: hg19 chr9:71,650,479-71,693,993 Size: 43,515 Total Exon Count: 5 Strand: + Coding Region Position: hg19 chr9:71,650,699-71,687,678 Size: 36,980 Coding Exon Count: 5
ID:FRDA_HUMAN DESCRIPTION: RecName: Full=Frataxin, mitochondrial; EC=1.16.3.1; AltName: Full=Friedreich ataxia protein; Short=Fxn; Contains: RecName: Full=Frataxin intermediate form; Short=i-FXN; Contains: RecName: Full=Frataxin(56-210); AltName: Full=m56-FXN; Contains: RecName: Full=Frataxin(78-210); AltName: Full=d-FXN; AltName: Full=m78-FXN; Contains: RecName: Full=Frataxin mature form; AltName: Full=Frataxin(81-210); AltName: Full=m81-FXN; Flags: Precursor; FUNCTION: Promotes the biosynthesis of heme and assembly and repair of iron-sulfur clusters by delivering Fe(2+) to proteins involved in these pathways. May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in vitro ferroxidase activity. May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems. Modulates the RNA-binding activity of ACO1. CATALYTIC ACTIVITY: 4 Fe(2+) + 4 H(+) + O(2) = 4 Fe(3+) + 2 H(2)O. SUBUNIT: Monomer (probable predominant form). Oligomer. Monomers and polymeric aggregates of >1 MDa have been isolated from mitochondria. A small fraction of heterologous overexpressed recombinant frataxin forms high-molecular wight aggregates that incoroprate iron. Interacts with LYRM4 AND HSPA9. Interacts with ACO1. Interacts with ISCU isoform 1 and isoform 2. Interacts with FECH; one iron-bound FXN monomer seems to interact with a FECH homodimer. Interacts with SDHA and SDHB. Interacts with ACO2; the interaction is dependent on citrate (By similarity). SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion. Note=PubMed:18725397 reports localization exclusively in mitochondria. TISSUE SPECIFICITY: Expressed in the heart, peripheral blood lymphocytes and dermal fibroblasts. PTM: Processed in two steps by mitochondrial processing peptidase (MPP). MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to yield frataxin mature form (frataxin(81-210)) which is the predominant form. The additional forms, frataxin(56-210) and frataxin(78-210), seem to be produced when the normal maturation process is impaired; their physiological relevance is unsure. DISEASE: Defects in FXN are the cause of Friedreich ataxia (FRDA) [MIM:229300]. FRDA is an autosomal recessive, progressive degenerative disease characterized by neurodegeneration and cardiomyopathy it is the most common inherited ataxia. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe. In most patients, FRDA is due to GAA triplet repeat expansions in the first intron of the frataxin gene. But in some cases the disease is due to mutations in the coding region. MISCELLANEOUS: The unusual migration profile of mature frataxin on SDS-PAGE due to its acidic N-terminus most likely contributed to conflicting reports for the N-terminus of the mature protein. Unlike prokaryotic and yeast frataxin homologs, which self- assemble at high iron concentrations, oligomerization of human frataxin is not induced by iron. The existence of a specialized mitochondrial ferritin in mammalia (FTMT) is suggesting that iron storage would be redundant function, at least in mammalian mitochondria. SIMILARITY: Belongs to the frataxin family. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FXN";
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Genetic Association Studies of Complex Diseases and Disorders
Genetic Association Database (archive): FXN CDC HuGE Published Literature: FXN Positive Disease Associations: diabetes, type 2 Related Studies:
diabetes, type 2 Shadrina MI et al. 2002, Association of polymorphic trinucleotide repeat (GAA)n of the Frataxin gene with diabetes mellitus type 2 in the Moscow population trans Sviaz' polimorfnogo trinukleotidnogo povtora (GAA)n v gene Frataksina s sakharnym diabetom tipa 2 v Moscovskoi popul, Molekuliarnaia biologiia. 2002 Jan-Feb;36(1):37-9.
[PubMed 11862710]
diabetes, type 2 Ristow M et al. 1998, An association between NIDDM and a GAA trinucleotide repeat polymorphism in the X25/frataxin (Friedreich's ataxia) gene., Diabetes. 1998 May;47(5):851-4.
[PubMed 9588463]
We conclude that the X25/frataxin GAA repeat polymorphism is associated with NIDDM in a frequency higher than any other mutation heretofore described. Further studies are needed to elucidate the possible role of frataxin in the pathogenesis of NIDDM.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q16595
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0006783 heme biosynthetic process GO:0006811 ion transport GO:0006879 cellular iron ion homeostasis GO:0008284 positive regulation of cell proliferation GO:0010039 response to iron ion GO:0010722 regulation of ferrochelatase activity GO:0016226 iron-sulfur cluster assembly GO:0016540 protein autoprocessing GO:0018283 iron incorporation into metallo-sulfur cluster GO:0030307 positive regulation of cell growth GO:0043066 negative regulation of apoptotic process GO:0043085 positive regulation of catalytic activity GO:0044281 small molecule metabolic process GO:0051349 positive regulation of lyase activity GO:0055072 iron ion homeostasis GO:0055114 oxidation-reduction process GO:0070301 cellular response to hydrogen peroxide GO:0090201 negative regulation of release of cytochrome c from mitochondria GO:1904231 positive regulation of succinate dehydrogenase activity GO:1904234 positive regulation of aconitate hydratase activity
U43747 - Human frataxin (FRDA) mRNA, complete cds. JD487773 - Sequence 468797 from Patent EP1572962. JD325105 - Sequence 306129 from Patent EP1572962. JD164099 - Sequence 145123 from Patent EP1572962. BC048097 - Homo sapiens frataxin, mRNA (cDNA clone MGC:57199 IMAGE:5300379), complete cds. BC023633 - Homo sapiens frataxin, mRNA (cDNA clone MGC:23075 IMAGE:4842134), complete cds. JD141635 - Sequence 122659 from Patent EP1572962. CU690546 - Synthetic construct Homo sapiens gateway clone IMAGE:100020799 5' read FXN mRNA. HQ447980 - Synthetic construct Homo sapiens clone IMAGE:100071347; CCSB010735_02 frataxin (FXN) gene, encodes complete protein. KJ896828 - Synthetic construct Homo sapiens clone ccsbBroadEn_06222 FXN gene, encodes complete protein. KJ905196 - Synthetic construct Homo sapiens clone ccsbBroadEn_14646 FXN gene, encodes complete protein. KR710950 - Synthetic construct Homo sapiens clone CCSBHm_00018350 FXN (FXN) mRNA, encodes complete protein. KR710951 - Synthetic construct Homo sapiens clone CCSBHm_00018360 FXN (FXN) mRNA, encodes complete protein. KU178079 - Homo sapiens frataxin isoform 1 (FXN) mRNA, partial cds. KU178080 - Homo sapiens frataxin isoform 3 (FXN) mRNA, complete cds, alternatively spliced. AK308620 - Homo sapiens cDNA, FLJ98661. JD337362 - Sequence 318386 from Patent EP1572962. JD123119 - Sequence 104143 from Patent EP1572962. JD511288 - Sequence 492312 from Patent EP1572962. JD306955 - Sequence 287979 from Patent EP1572962. JD233188 - Sequence 214212 from Patent EP1572962. JD172824 - Sequence 153848 from Patent EP1572962. JD467622 - Sequence 448646 from Patent EP1572962. JD235685 - Sequence 216709 from Patent EP1572962. JD508968 - Sequence 489992 from Patent EP1572962. JD048616 - Sequence 29640 from Patent EP1572962. JD440717 - Sequence 421741 from Patent EP1572962. JD432358 - Sequence 413382 from Patent EP1572962. JD512734 - Sequence 493758 from Patent EP1572962. JD425595 - Sequence 406619 from Patent EP1572962. JD395614 - Sequence 376638 from Patent EP1572962. JD135929 - Sequence 116953 from Patent EP1572962. JD105596 - Sequence 86620 from Patent EP1572962. JD158815 - Sequence 139839 from Patent EP1572962. JD275672 - Sequence 256696 from Patent EP1572962. JD267438 - Sequence 248462 from Patent EP1572962. DQ601957 - Homo sapiens piRNA piR-40023, complete sequence. JD446880 - Sequence 427904 from Patent EP1572962. JD443416 - Sequence 424440 from Patent EP1572962.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein Q16595 (Reactome details) participates in the following event(s):
R-HSA-1299475 TIMM23 PAM translocates proteins from the mitochndrial intermebrane space to the mitochondrial matrix R-HSA-1299480 Precursor proteins enter TIMM23 PAM R-HSA-1362416 Frataxin binds iron R-HSA-1299478 MPP cleaves targeting peptide (presequence) of matrix precursors R-HSA-1268020 Mitochondrial protein import R-HSA-1362409 Mitochondrial iron-sulfur cluster biogenesis R-HSA-392499 Metabolism of proteins R-HSA-1430728 Metabolism