Details for: FXN

Gene ID: 2395

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: FXN

Ensembl ID: ENSG00000165060

Description: frataxin

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 3.94
    rCSI 3.55%
    PRS 91.21
  • hematopoietic precursor cell CL0008001
    CSI 3.73
    rCSI 3.84%
    PRS 96.63
  • erythroid progenitor cell CL0000038
    CSI 3.44
    rCSI 19.71%
    PRS 93.72
  • common myeloid progenitor CL0000049
    CSI 3.33
    rCSI 2.7%
    PRS 93.28
  • plasmacytoid dendritic cell, human CL0001058
    CSI 3.02
    rCSI 2.11%
    PRS 95.01
  • hematopoietic stem cell CL0000037
    CSI 2.93
    rCSI 1.95%
    PRS 93.54
  • plasmablast CL0000980
    CSI 2.93
    rCSI 2.3%
    PRS 94.04
  • choroid plexus epithelial cell CL0000706
    CSI 2.91
    rCSI 4.77%
    PRS 86.37
  • primitive red blood cell CL0002355
    CSI 2.84
    rCSI 15.34%
    PRS 93.21
  • neural crest cell CL0011012
    CSI 2.8
    rCSI 2.21%
    PRS 86.41
  • placental villous trophoblast CL2000060
    CSI 2.56
    rCSI 3.95%
    PRS 90.58
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.52
    rCSI 2.18%
    PRS 94.04
  • ciliated epithelial cell CL0000067
    CSI 2.37
    rCSI 2.09%
    PRS 84.57
  • activated type II NK T cell CL0000931
    CSI 2.37
    rCSI 2.67%
    PRS 97.55
  • mucous neck cell CL0000651
    CSI 2.15
    rCSI 3.1%
    PRS 94.39
  • basal cell CL0000646
    CSI 2.09
    rCSI 2.79%
    PRS 89.8
  • retinal bipolar neuron CL0000748
    CSI 2.06
    rCSI 3.87%
    PRS 85.1
  • stem cell CL0000034
    CSI 2
    rCSI 1.93%
    PRS 88.78
  • promyelocyte CL0000836
    CSI 1.97
    rCSI 2.83%
    PRS 93.91
  • periportal region hepatocyte CL0019026
    CSI 1.88
    rCSI 7.3%
    PRS 89.26
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 1.87
    rCSI 11.03%
    PRS 81.69
  • mesenchymal cell CL0008019
    CSI 1.83
    rCSI 4.65%
    PRS 87.94
  • sst GABAergic cortical interneuron CL4023017
    CSI 1.75
    rCSI 2.26%
    PRS 82.34
  • club cell CL0000158
    CSI 1.72
    rCSI 2.52%
    PRS 88.52
  • cardiac muscle cell CL0000746
    CSI 1.72
    rCSI 2.47%
    PRS 85.26
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 1.71
    rCSI 6.17%
    PRS 79.39
  • ependymal cell CL0000065
    CSI 1.6
    rCSI 3.24%
    PRS 76.53
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.55
    rCSI 2.73%
    PRS 80.66
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.49
    rCSI 3.35%
    PRS 81.5
  • radial glial cell CL0000681
    CSI 1.49
    rCSI 2.07%
    PRS 90.81
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.32
    rCSI 2.13%
    PRS 82.29
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.32
    rCSI 2.21%
    PRS 81.32
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 1.25
    rCSI 3.91%
    PRS 84.16
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.97
    rCSI 3.04%
    PRS 82.48
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 0.92
    rCSI 2.23%
    PRS 79.14
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.87
    rCSI 3.27%
    PRS 81.48
  • erythroblast CL0000765
    CSI 0.86
    rCSI 2.28%
    PRS 92.7
  • direct pathway medium spiny neuron CL4023026
    CSI 0.29
    rCSI 6.88%
    PRS 79.08
  • indirect pathway medium spiny neuron CL4023029
    CSI 0.25
    rCSI 6.1%
    PRS 79.19

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [FXN](/details-gene/2395) is a protein-coding gene that produces frataxin, a highly conserved mitochondrial protein essential for cellular iron metabolism. The primary function of frataxin involves acting as an iron chaperone, facilitating the biosynthesis of iron-sulfur (Fe-S) clusters, which are critical cofactors for numerous enzymes involved in mitochondrial respiration and the citric acid cycle. [FXN](/details-gene/2395) is also implicated in the heme biosynthetic pathway. **Overall**, its expression is most significant in hematopoietic progenitor cells, particularly those of the erythroid lineage. Clinically, deficiency in frataxin, typically caused by a GAA triplet repeat expansion in the first intron of [FXN](/details-gene/2395), leads to the autosomal recessive neurodegenerative disorder Friedreich ataxia ([229300](https://omim.org/entry/229300)) [Link](https://doi.org/10.1126/science.271.5254.1423). ## Cellular Roles and Expression Landscape The expression profile of [FXN](/details-gene/2395) highlights its fundamental role in cell types with high metabolic demands and active proliferation, particularly within the hematopoietic system. - **Hematopoietic Progenitors:** **Overall**, [FXN](/details-gene/2395) shows the highest significance in early hematopoietic lineages. It is a top marker in [megakaryocyte-erythroid progenitor cell](/details-cell/CL0000050) (CSI: 3.94), [hematopoietic precursor cell](/details-cell/CL0008001) (CSI: 3.73), [erythroid progenitor cell](/details-cell/CL0000038) (CSI: 3.44), and [common myeloid progenitor](/details-cell/CL0000049) (CSI: 3.33). This strong association with erythroid development is consistent with its crucial role in intracellular iron ion homeostasis ([GO:0006879](https://www.ebi.ac.uk/QuickGO/term/GO:0006879)) and the heme biosynthetic process ([GO:0006783](https://www.ebi.ac.uk/QuickGO/term/GO:0006783)), as these cells are primary sites of hemoglobin synthesis. - **Immune and Epithelial Cells:** The gene also shows significant expression in specific immune cell populations such as [plasmacytoid dendritic cell, human](/details-cell/CL0001058) (CSI: 3.02) and [plasmablast](/details-cell/CL0000980) (CSI: 2.93), suggesting a role in supporting the high energetic needs of these specialized cells. Furthermore, its notable presence in metabolically active epithelial cells like [choroid plexus epithelial cell](/details-cell/CL0000706) (CSI: 2.91) and [placental villous trophoblast](/details-cell/CL2000060) (CSI: 2.56) underscores its widespread importance in maintaining mitochondrial function across diverse tissues. ## Pathways and Molecular Function [FXN](/details-gene/2395) encodes frataxin, a protein centrally located in mitochondrial iron metabolism. Its molecular functions are integral to cellular bioenergetics and viability. - **Iron-Sulfur Cluster Assembly:** The canonical function of frataxin is its role in iron-sulfur cluster assembly ([GO:0016226](https://www.ebi.ac.uk/QuickGO/term/GO:0016226)). It acts as an iron chaperone ([GO:0034986](https://www.ebi.ac.uk/QuickGO/term/GO:0034986)) that delivers iron to the core assembly machinery for both [2fe-2s] ([GO:0044571](https://www.ebi.ac.uk/QuickGO/term/GO:0044571)) and [4fe-4s] ([GO:0044572](https://www.ebi.ac.uk/QuickGO/term/GO:0044572)) clusters [Link](https://doi.org/10.1021/ja027967i). These clusters are essential for the function of numerous proteins, particularly those in the respiratory electron transport chain ([R-HSA-611105](https://reactome.org/content/detail/R-HSA-611105)) and the citric acid cycle ([R-HSA-71403](https://reactome.org/content/detail/R-HSA-71403)). - **Heme Biosynthesis:** Frataxin is also involved in the heme biosynthetic process ([GO:0006783](https://www.ebi.ac.uk/QuickGO/term/GO:0006783)) by supplying iron to ferrochelatase, the enzyme that catalyzes the final step of heme synthesis [Link](https://doi.org/10.1074/jbc.c400107200). This function directly explains its high expression significance in erythroid precursors, which are dedicated to producing vast amounts of hemoglobin. - **Cellular Homeostasis and Stress Response:** By maintaining the integrity of mitochondrial Fe-S proteins, [FXN](/details-gene/2395) plays a protective role against oxidative stress. It is involved in the cellular response to hydrogen peroxide ([GO:0070301](https://www.ebi.ac.uk/QuickGO/term/GO:0070301)) and the negative regulation of the apoptotic process ([GO:0043066](https://www.ebi.ac.uk/QuickGO/term/GO:0043066)), likely by preventing mitochondrial dysfunction and the subsequent release of pro-apoptotic factors like cytochrome c. ## Research Directions The central role of [FXN](/details-gene/2395) in mitochondrial iron metabolism and its direct link to Friedreich ataxia present clear avenues for future research. **Proposed Hypotheses:** 1. Deficiency of [FXN](/details-gene/2395) in [hematopoietic stem cell](/details-cell/CL0000037)s and downstream progenitors not only impairs hemoglobinization due to failed heme synthesis but also creates a bioenergetic crisis that blocks effective differentiation and promotes apoptosis, contributing directly to the hematological abnormalities sometimes seen in Friedreich ataxia. 2. The significant expression of [FXN](/details-gene/2395) in [plasmacytoid dendritic cell, human](/details-cell/CL0001058) suggests that frataxin deficiency may impair their unique capacity for high-level type I interferon production upon viral sensing, a process that is energetically demanding. This could represent an underappreciated aspect of immune dysregulation in Friedreich ataxia. **Suggested Experimental Approach:** To test the first hypothesis regarding hematopoietic dysfunction, one could generate an *in vitro* model using CRISPR-i (interference) to achieve partial knockdown of [FXN](/details-gene/2395) in human CD34+ [hematopoietic stem cell](/details-cell/CL0000037)s. These modified cells would then be cultured under conditions promoting erythroid differentiation. The experimental readouts would include: * **Flow cytometry:** To track the progression through erythroid differentiation stages (e.g., using CD71 and CD235a markers) and to quantify apoptosis via Annexin V/PI staining at each stage. * **RNA-sequencing:** To profile transcriptomic changes and identify dysregulated pathways related to metabolism, differentiation, and cell death. * **Functional Assays:** Seahorse XF analysis to measure mitochondrial respiration (oxygen consumption rate) and glycolysis (extracellular acidification rate), providing a direct assessment of the cells' bioenergetic status. **Therapeutic Potential:** Given that Friedreich ataxia is a loss-of-function monogenic disorder, the therapeutic strategy for [FXN](/details-gene/2395) is focused on **activation** or **replacement**, not inhibition. [FXN](/details-gene/2395) is a poor candidate for inhibitory drugs, as this would mimic the disease state and likely be toxic. Current and future therapeutic approaches aim to increase the amount of functional frataxin protein in affected cells. This includes AAV-mediated gene therapy to deliver a functional copy of the [FXN](/details-gene/2395) gene, the development of small molecules that can overcome the transcriptional silencing caused by the GAA repeat expansion, and protein replacement therapies.

Genular Protein ID: 324811028

Symbol: FRDA_HUMAN

Name: Friedreich ataxia protein

UniProtKB Accession Codes:

Q16595 A8MXJ6 C9JJ89 O15545 O95656 Q15294 Q5VZ01

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CORUM 1 CTD 1 ChEBI 5 ChEMBL 1 ChiTaRS 1 ComplexPortal 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 6 EC 1 EMBL 17 EMDB 4 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 38 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 2 OGP 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 15 PDBsum 15 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 Reactome 4 RefSeq 3 Rhea 1 SABIO-RK 1 SASBDB 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TopDownProteomics 2 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8596916

Title: Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.

PubMed ID: 8596916

DOI: 10.1126/science.271.5254.1423

PubMed ID: 15164053

Title: DNA sequence and analysis of human chromosome 9.

PubMed ID: 15164053

DOI: 10.1038/nature02465

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 18725397

Title: The in vivo mitochondrial two-step maturation of human frataxin.

PubMed ID: 18725397

DOI: 10.1093/hmg/ddn244

PubMed ID: 17468497

Title: In vivo maturation of human frataxin.

PubMed ID: 17468497

DOI: 10.1093/hmg/ddm102

PubMed ID: 20053667

Title: Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin.

PubMed ID: 20053667

DOI: 10.1093/hmg/ddp592

PubMed ID: 9302253

Title: Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes.

PubMed ID: 9302253

DOI: 10.1093/hmg/6.11.1771

PubMed ID: 9241270

Title: Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin.

PubMed ID: 9241270

DOI: 10.1038/ng0897-345

PubMed ID: 10545606

Title: Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase.

PubMed ID: 10545606

DOI: 10.1093/hmg/8.12.2255

PubMed ID: 10428860

Title: Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase.

PubMed ID: 10428860

DOI: 10.1074/jbc.274.32.22763

PubMed ID: 11020385

Title: Two-step processing of human frataxin by mitochondrial processing peptidase. Precursor and intermediate forms are cleaved at different rates.

PubMed ID: 11020385

DOI: 10.1074/jbc.m006539200

PubMed ID: 11823441

Title: Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia.

PubMed ID: 11823441

DOI: 10.1093/hmg/11.3.217

PubMed ID: 12755598

Title: Structure of frataxin iron cores: an X-ray absorption spectroscopic study.

PubMed ID: 12755598

DOI: 10.1021/bi027021l

PubMed ID: 12785837

Title: Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins.

PubMed ID: 12785837

DOI: 10.1021/ja027967i

PubMed ID: 15123683

Title: Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis.

PubMed ID: 15123683

DOI: 10.1074/jbc.c400107200

PubMed ID: 15247478

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

PubMed ID: 15247478

DOI: 10.1126/science.1098991

PubMed ID: 15641778

Title: Assembly of human frataxin is a mechanism for detoxifying redox-active iron.

PubMed ID: 15641778

DOI: 10.1021/bi048459j

PubMed ID: 15961414

Title: Frataxin interacts functionally with mitochondrial electron transport chain proteins.

PubMed ID: 15961414

DOI: 10.1093/hmg/ddi214

PubMed ID: 16239244

Title: Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells.

PubMed ID: 16239244

DOI: 10.1093/hmg/ddi393

PubMed ID: 16091420

Title: Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2.

PubMed ID: 16091420

DOI: 10.1242/jcs.02516

PubMed ID: 15581888

Title: Supramolecular assemblies of human frataxin are formed via subunit-subunit interactions mediated by a non-conserved amino-terminal region.

PubMed ID: 15581888

DOI: 10.1016/j.jmb.2004.10.074

PubMed ID: 16608849

Title: A pool of extramitochondrial frataxin that promotes cell survival.

PubMed ID: 16608849

DOI: 10.1074/jbc.m511960200

PubMed ID: 17331979

Title: Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones.

PubMed ID: 17331979

DOI: 10.1093/hmg/ddm038

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21298097

Title: Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex.

PubMed ID: 21298097

DOI: 10.1371/journal.pone.0016199

PubMed ID: 24971490

Title: Human frataxin activates Fe-S cluster biosynthesis by facilitating sulfur transfer chemistry.

PubMed ID: 24971490

DOI: 10.1021/bi500532e

PubMed ID: 25944712

Title: N-terminome analysis of the human mitochondrial proteome.

PubMed ID: 25944712

DOI: 10.1002/pmic.201400617

PubMed ID: 26702583

Title: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.

PubMed ID: 26702583

DOI: 10.1016/j.mito.2015.12.005

PubMed ID: 29576242

Title: Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly.

PubMed ID: 29576242

DOI: 10.1016/j.jinorgbio.2018.03.007

PubMed ID: 10900192

Title: Crystal structure of human frataxin.

PubMed ID: 10900192

DOI: 10.1074/jbc.c000407200

PubMed ID: 10903947

Title: Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin.

PubMed ID: 10903947

DOI: 10.1016/s0969-2126(00)00158-1

PubMed ID: 31101807

Title: Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.

PubMed ID: 31101807

DOI: 10.1038/s41467-019-09989-y

PubMed ID: 9150176

Title: Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion.

PubMed ID: 9150176

PubMed ID: 9779809

Title: Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies.

PubMed ID: 9779809

DOI: 10.1002/(sici)1096-8628(19981012)79:5<396::aid-ajmg13>3.3.co;2-b

PubMed ID: 10732799

Title: The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene.

PubMed ID: 10732799

DOI: 10.1007/s100480050037

PubMed ID: 9989622

Title: Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes.

PubMed ID: 9989622

DOI: 10.1002/1531-8249(199902)45:2<200::aid-ana10>3.0.co;2-u

PubMed ID: 10874325

Title: A novel missense mutation (L198R) in the Friedreich's ataxia gene.

PubMed ID: 10874325

DOI: 10.1002/1098-1004(200007)16:1<95::aid-humu29>3.0.co;2-e

PubMed ID: 19629184

Title: The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia.

PubMed ID: 19629184

DOI: 10.1371/journal.pone.0006379

Sequence Information:

  • Length: 210
  • Mass: 23135
  • Checksum: ECC81738779308CF
  • Sequence:
    • MWTLGRRAVA GLLASPSPAQ AQTLTRVPRP AELAPLCGRR GLRTDIDATC TPRRASSNQR 
GLNQIWNVKK QSVYLMNLRK SGTLGHPGSL DETTYERLAE ETLDSLAEFF EDLADKPYTF 
EDYDVSFGSG VLTVKLGGDL GTYVINKQTP NKQIWLSSPS SGPKRYDWTG KNWVYSHDGV 
SLHELLAAEL TKALKTKLDL SSLAYSGKDA