TMLHE Gene

Name	trimethyllysine hydroxylase, epsilon
Description	This gene encodes the protein trimethyllysine dioxygenase which is the first enzyme in the carnitine biosynthesis pathway. Carnitine play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane. The encoded protein converts trimethyllysine into hydroxytrimethyllysine. A pseudogene of this gene is found on chromosome X. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTrimethyllysine hydroxylase epsilon (TMLHE) is the enzyme that catalyzes the stereospecific hydroxylation of (2S)-N‑trimethyllysine to (2S,3S)-3‑hydroxy‑N‑trimethyllysine, which is the first and rate‐limiting step in carnitine biosynthesis. Molecular cloning studies have revealed that the TMLHE gene gives rise to multiple alternatively spliced isoforms, one of which lacks key C‑terminal determinants and may even act as a negative regulator of enzyme activity. These observations underscore the importance of conserved catalytic residues and proper transcript regulation for optimal TMLHE function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n \n \nRecent large‐scale genetic analyses have identified deletions and missense mutations in TMLHE among males with autism spectrum disorders. In these cases, TMLHE deficiency leads to the accumulation of its substrate and a decrease in downstream carnitine pathway metabolites, suggesting that dysregulation of carnitine metabolism may contribute as a low-penetrance risk factor for autism. These findings support a role for rare X‑linked TMLHE variants in the etiology of neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n \n \nFurther biochemical and genomic studies have elaborated on the critical binding sites required for TMLHE’s enzyme activity – including residues essential for coordinating its Fe(II) cofactor, 2-oxoglutarate cosubstrate, and substrate interaction – while additional research has reported complex genomic rearrangements involving TMLHE, such as duplications linked with haemophilia A. Collectively, these insights highlight both the intricate transcriptional and post-transcriptional control of TMLHE and its pivotal role in carnitine biosynthesis with broader implications for human disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jlenia Monfregola, Armando Cevenini, Antonio Terracciano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.20332"}], "href": "https://doi.org/10.1002/jcp.20332"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15754339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15754339"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jlenia Monfregola, Gennaro Napolitano, Ivan Conte, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2007.02.012"}], "href": "https://doi.org/10.1016/j.gene.2007.02.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17408883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17408883"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Patricia B S Celestino-Soper, Chad A Shaw, Stephan J Sanders, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr363"}], "href": "https://doi.org/10.1093/hmg/ddr363"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21865298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21865298"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Patrícia B S Celestino-Soper, Sara Violante, Emily L Crawford, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1120210109"}], "href": "https://doi.org/10.1073/pnas.1120210109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22566635"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22566635"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "C Nava, F Lamari, D Héron, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transl Psychiatry (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/tp.2012.102"}], "href": "https://doi.org/10.1038/tp.2012.102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23092983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23092983"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Changming Chen, Xiaoling Xie, Xi Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Thromb Haemost (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1160/TH17-01-0046"}], "href": "https://doi.org/10.1160/TH17-01-0046"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28492696"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28492696"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yali Wang, Y Vijayendar Reddy, Abbas H K Al Temimi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Investigating the active site of human trimethyllysine hydroxylase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BCJ20180857"}], "href": "https://doi.org/10.1042/BCJ20180857"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30898847"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30898847"}]}]}]}
Synonyms	TMLH, TMLD, BBOX2, XAP130, AUTSX6, TMLHED
Proteins	TMLH_HUMAN
NCBI Gene ID	55217
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

TMLHE has 4,858 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 119 datasets.

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

If available, associations are ranked by standardized value

Harmonizome 3.0

TMLHE Gene

Functional Associations

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

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by TMLHE gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of TMLHE 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 TMLHE 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 TMLHE 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 TMLHE 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 TMLHE 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 TMLHE 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 TMLHE 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 TMLHE 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 TMLHE 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 TMLHE gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of TMLHE gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with TMLHE protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TMLHE gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of TMLHE 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 TMLHE gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with TMLHE gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing TMLHE 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 TMLHE gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing TMLHE protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing TMLHE protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing TMLHE 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 TMLHE 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 TMLHE 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 TMLHE 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 TMLHE gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with TMLHE gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with TMLHE gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with TMLHE gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of TMLHE 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 TMLHE gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving TMLHE gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with TMLHE 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 TMLHE 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 TMLHE gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with TMLHE gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for TMLHE protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at TMLHE 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 TMLHE gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of TMLHE gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.