FBXL4 Gene

HGNC Family	F-boxes (FBX)
Name	F-box and leucine-rich repeat protein 4
Description	This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FBXL4 is a nuclear‐encoded F‐box and leucine‐rich repeat protein that is targeted to mitochondria, where it localizes within the intermembrane space and forms part of a high–molecular weight complex. Several studies have implicated FBXL4 as a pivotal regulator of mitochondrial homeostasis. Notably, FBXL4 is essential for maintaining mitochondrial DNA (mtDNA) integrity and stability, ensuring proper levels of mtDNA and optimal oxidative phosphorylation. Loss‐of–function mutations in FBXL4 disrupt bioenergetic processes, leading to decreased oxygen consumption, reduced mtDNA content, and extensive mitochondrial network fragmentation. Such dysfunction is manifest clinically as severe, early–onset encephalomyopathy characterized by lactic acidosis, muscular hypotonia, developmental delays, and multisystem defects."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in mtDNA maintenance, emerging evidence indicates that FBXL4 is involved in regulating mitochondrial dynamics. FBXL4 facilitates mitochondrial fusion, as demonstrated by the observation that wild–type FBXL4 overexpression induces hyperfusion, whereas pathogenic variants lead to reduced fusion rates, contributing to aberrant mitochondrial morphology and increased turnover via autophagy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, in a broader cellular context, FBXL4 may participate in substrate recognition and protein turnover as part of a Skp1–Cullin–F–box (SCF) ubiquitin ligase complex, thereby indirectly influencing mitochondrial and cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Animal studies further corroborate the central role of FBXL4 in preserving mitochondrial mass by preventing excessive removal of mitochondria through autophagy and highlight its indispensable function in bioenergetic homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, the collective data demonstrate that FBXL4 is a critical mitochondrial protein governing mtDNA maintenance, energy production, and mitochondrial dynamics. Disruption of FBXL4 function leads to severe mitochondrial disease, underscoring its importance in maintaining cellular bioenergetic integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xiaowu Gai, Daniele Ghezzi, Mark A Johnson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2013.07.016"}], "href": "https://doi.org/10.1016/j.ajhg.2013.07.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23993194"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23993194"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Penelope E Bonnen, John W Yarham, Arnaud Besse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2013.07.017"}], "href": "https://doi.org/10.1016/j.ajhg.2013.07.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23993193"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23993193"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ayman W El-Hattab, Hongzheng Dai, Mohammed Almannai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular and clinical spectra of FBXL4 deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.23341"}], "href": "https://doi.org/10.1002/humu.23341"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28940506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28940506"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "H Dai, V W Zhang, A W El-Hattab, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.12894"}], "href": "https://doi.org/10.1111/cge.12894"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27743463"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27743463"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Engin Köse, Melis Köse, Selvinaz Edizer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Different clinical presentation in a patient with two novel pathogenic variants of the FBXL4 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Turk J Pediatr (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.24953/turkjped.2020.04.016"}], "href": "https://doi.org/10.24953/turkjped.2020.04.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32779419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32779419"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Rasha Sabouny, Rachel Wong, Laurie Lee-Glover, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the C584R variant in the mtDNA depletion syndrome gene FBXL4, reveals a novel role for FBXL4 as a regulator of mitochondrial fusion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Basis Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2019.165536"}], "href": "https://doi.org/10.1016/j.bbadis.2019.165536"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31442532"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31442532"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ayman W El-Hattab, Jehan Suleiman, Mohammed Almannai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial dynamics: Biological roles, molecular machinery, and related diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2018.10.003"}], "href": "https://doi.org/10.1016/j.ymgme.2018.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30361041"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30361041"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Capucine Van Rechem, Joshua C Black, Tarek Abbas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The SKP1-Cul1-F-box and leucine-rich repeat protein 4 (SCF-FbxL4) ubiquitin ligase regulates lysine demethylase 4A (KDM4A)/Jumonji domain-containing 2A (JMJD2A) protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.273508"}], "href": "https://doi.org/10.1074/jbc.M111.273508"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21757720"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21757720"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "David Alsina, Oleksandr Lytovchenko, Aleksandra Schab, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FBXL4 deficiency increases mitochondrial removal by autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/emmm.201911659"}], "href": "https://doi.org/10.15252/emmm.201911659"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32525278"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32525278"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Martina Huemer, Daniela Karall, Anna Schossig, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inherit Metab Dis (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10545-015-9836-6"}], "href": "https://doi.org/10.1007/s10545-015-9836-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25868664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25868664"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Chaoping Hu, Xihua Li, Lei Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical and molecular characterization of pediatric mitochondrial disorders in south of China."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2020.103898"}], "href": "https://doi.org/10.1016/j.ejmg.2020.103898"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32348839"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32348839"}]}]}]}
Synonyms	MTDPS13
Proteins	FBXL4_HUMAN
NCBI Gene ID	26235
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

FBXL4 has 5,296 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 113 datasets.

Click the + buttons to view associations for FBXL4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

FBXL4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of FBXL4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of FBXL4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of FBXL4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of FBXL4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of FBXL4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of FBXL4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of FBXL4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of FBXL4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of FBXL4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of FBXL4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of FBXL4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of FBXL4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of FBXL4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of FBXL4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of FBXL4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with FBXL4 gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with FBXL4 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of FBXL4 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing FBXL4 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of FBXL4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing FBXL4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing FBXL4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing FBXL4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing FBXL4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with FBXL4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with FBXL4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of FBXL4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with FBXL4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with FBXL4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of FBXL4 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by FBXL4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving FBXL4 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with FBXL4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with FBXL4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with FBXL4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with FBXL4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with FBXL4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at FBXL4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of FBXL4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of FBXL4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.