Details for: TMLHE

Gene ID: 55217

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: TMLHE

Ensembl ID: ENSG00000185973

Description: trimethyllysine hydroxylase, epsilon

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • alveolar macrophage CL0000583
    CSI 5.67
    rCSI 9.33%
    PRS 92.25
  • immature B cell CL0000816
    CSI 4.85
    rCSI 3.6%
    PRS 95.87
  • ependymal cell CL0000065
    CSI 4.8
    rCSI 9.74%
    PRS 73.38
  • astrocyte of the cerebral cortex CL0002605
    CSI 4.46
    rCSI 10.01%
    PRS 78.29
  • alveolar adventitial fibroblast CL4028006
    CSI 4.29
    rCSI 6.77%
    PRS 91.36
  • renal alpha-intercalated cell CL0005011
    CSI 4.2
    rCSI 5.62%
    PRS 93.7
  • precursor B cell CL0000817
    CSI 3.9
    rCSI 3.42%
    PRS 94.14
  • pro-B cell CL0000826
    CSI 3.77
    rCSI 3.12%
    PRS 91.7
  • early lymphoid progenitor CL0000936
    CSI 3.73
    rCSI 3.28%
    PRS 93.32
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 3.7
    rCSI 13.33%
    PRS 75.87
  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 3.59
    rCSI 2.39%
    PRS 95.86
  • kidney connecting tubule epithelial cell CL1000768
    CSI 3.5
    rCSI 8.87%
    PRS 84.54
  • naive B cell CL0000788
    CSI 3.32
    rCSI 2.85%
    PRS 93.8
  • melanocyte CL0000148
    CSI 3.17
    rCSI 2.35%
    PRS 87.06
  • glial cell CL0000125
    CSI 3.16
    rCSI 12.01%
    PRS 84.19
  • mesothelial cell CL0000077
    CSI 3.08
    rCSI 12.04%
    PRS 74.08
  • Kupffer cell CL0000091
    CSI 2.97
    rCSI 6.78%
    PRS 91.59
  • interneuron CL0000099
    CSI 2.94
    rCSI 5.91%
    PRS 84.52
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 2.85
    rCSI 4.04%
    PRS 88.54
  • retinal bipolar neuron CL0000748
    CSI 2.75
    rCSI 5.15%
    PRS 82.37
  • mesodermal cell CL0000222
    CSI 2.75
    rCSI 3.3%
    PRS 89.35
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 2.73
    rCSI 2.11%
    PRS 93.39
  • hepatic stellate cell CL0000632
    CSI 2.69
    rCSI 10.06%
    PRS 86.05
  • choroid plexus epithelial cell CL0000706
    CSI 2.55
    rCSI 4.17%
    PRS 83.78
  • lung secretory cell CL1000272
    CSI 2.42
    rCSI 5.99%
    PRS 91.24
  • Mueller cell CL0000636
    CSI 2.42
    rCSI 5.52%
    PRS 84.21
  • neural crest cell CL0011012
    CSI 2.34
    rCSI 1.85%
    PRS 83.73
  • adipocyte CL0000136
    CSI 2.27
    rCSI 2.92%
    PRS 82.66
  • blood vessel endothelial cell CL0000071
    CSI 2.23
    rCSI 4.63%
    PRS 88.95
  • stem cell CL0000034
    CSI 2.18
    rCSI 2.1%
    PRS 86.58
  • fibroblast of cardiac tissue CL0002548
    CSI 2.18
    rCSI 10.43%
    PRS 91.34
  • renal interstitial pericyte CL1001318
    CSI 2.17
    rCSI 5.99%
    PRS 87.97
  • cardiac endothelial cell CL0010008
    CSI 2.17
    rCSI 8.74%
    PRS 91.07
  • sncg GABAergic cortical interneuron CL4023015
    CSI 2.14
    rCSI 3.44%
    PRS 78.83
  • CD14-positive monocyte CL0001054
    CSI 2.08
    rCSI 2.59%
    PRS 95.63
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 2.07
    rCSI 5.39%
    PRS 91.94
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 2.06
    rCSI 3.45%
    PRS 77.87
  • cardiac muscle cell CL0000746
    CSI 2.01
    rCSI 2.88%
    PRS 82.95
  • cerebral cortex endothelial cell CL1001602
    CSI 1.86
    rCSI 3.22%
    PRS 85.33
  • renal beta-intercalated cell CL0002201
    CSI 1.86
    rCSI 4.44%
    PRS 90.74
  • Bergmann glial cell CL0000644
    CSI 1.82
    rCSI 2.49%
    PRS 83.26
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 1.77
    rCSI 6.7%
    PRS 78.07
  • parietal epithelial cell CL1000452
    CSI 1.77
    rCSI 4.73%
    PRS 85.51
  • cardiac neuron CL0010022
    CSI 1.75
    rCSI 5.61%
    PRS 89.32
  • chondrocyte CL0000138
    CSI 1.72
    rCSI 2.73%
    PRS 85.94
  • Schwann cell CL0002573
    CSI 1.67
    rCSI 4.74%
    PRS 87.18
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.6
    rCSI 3.88%
    PRS 75.67
  • direct pathway medium spiny neuron CL4023026
    CSI 1.58
    rCSI 37.9%
    PRS 75.69
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 1.58
    rCSI 1.91%
    PRS 94.81
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.54
    rCSI 3.99%
    PRS 87.92
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.54
    rCSI 37.08%
    PRS 75.82
  • lymphoid lineage restricted progenitor cell CL0000838
    CSI 1.46
    rCSI 5.68%
    PRS 97.69
  • regular atrial cardiac myocyte CL0002129
    CSI 1.41
    rCSI 4.54%
    PRS 87.24
  • myeloid dendritic cell CL0000782
    CSI 1.4
    rCSI 2.02%
    PRS 97.13
  • retinal ganglion cell CL0000740
    CSI 1.39
    rCSI 3.08%
    PRS 80.26
  • intermediate monocyte CL0002393
    CSI 1.31
    rCSI 1.98%
    PRS 94.24
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 1.21
    rCSI 7.15%
    PRS 78.32
  • L6b glutamatergic cortical neuron CL4023038
    CSI 1.14
    rCSI 3.55%
    PRS 79.16
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.11
    rCSI 1.96%
    PRS 77.25
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 1.07
    rCSI 3.34%
    PRS 80.85
  • regular ventricular cardiac myocyte CL0002131
    CSI 0.61
    rCSI 3.83%
    PRS 84.66
  • ON parasol ganglion cell CL4033052
    CSI 0.45
    rCSI 6.36%
    PRS 83.41
  • blood vessel smooth muscle cell CL0019018
    CSI 0.45
    rCSI 3.63%
    PRS 87.92
  • OFF midget ganglion cell CL4033047
    CSI 0.3
    rCSI 6.12%
    PRS 83.04
  • ON midget ganglion cell CL4033046
    CSI 0.3
    rCSI 6.11%
    PRS 82.29
  • medium spiny neuron CL1001474
    CSI 0.24
    rCSI 2.1%
    PRS 82.79

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 [TMLHE](/details-gene/55217) (trimethyllysine hydroxylase, epsilon) is a protein-coding gene located on the X chromosome that encodes the mitochondrial enzyme trimethyllysine dioxygenase. This enzyme catalyzes the first step in the carnitine biosynthesis pathway, a critical process for the transport of long-chain fatty acids into mitochondria for beta-oxidation. Consistent with its fundamental role in cellular energy metabolism, [TMLHE](/details-gene/55217) is broadly expressed across various cell lineages. It shows particularly high significance in metabolically active cells, including immune cells like the [alveolar macrophage](/details-cell/CL0000583) and developing B-lymphocytes, as well as in neural cells such as [ependymal cells](/details-cell/CL0000065) and [astrocytes](/details-cell/CL0002605). Clinically, mutations in [TMLHE](/details-gene/55217) are associated with trimethyllysine hydroxylase deficiency ([OMIM:300777](https://omim.org/entry/300777)) and have been linked to an increased risk for autism spectrum disorders ([OMIM:300872](https://omim.org/entry/300872)). ## Cellular Roles and Expression Landscape The expression profile of [TMLHE](/details-gene/55217) highlights its importance in cells with high metabolic demands across multiple tissues. **Overall**, the gene demonstrates the highest significance in the [alveolar macrophage](/details-cell/CL0000583) (CSI: 5.67), suggesting a critical role for carnitine-dependent fatty acid oxidation in fueling phagocytic and inflammatory functions in the lung. A prominent role in the immune system is further supported by its high significance throughout B cell development, from [early lymphoid progenitor](/details-cell/CL0000936) and [pro-B cell](/details-cell/CL0000826) stages to [immature B cell](/details-cell/CL0000816) (CSI: 4.85) and [naive B cell](/details-cell/CL0000788). This pattern indicates that carnitine biosynthesis is a key metabolic program supporting the energetic requirements of lymphocyte proliferation and maturation. Beyond the immune system, [TMLHE](/details-gene/55217) is also highly significant in the central nervous system and renal system. Its expression in [ependymal cell](/details-cell/CL0000065) (CSI: 4.80), [astrocyte of the cerebral cortex](/details-cell/CL0002605) (CSI: 4.46), and [L5 extratelencephalic projecting glutamatergic cortical neuron](/details-cell/CL4023041) is consistent with the brain's high energy consumption. In the kidney, its significance in [renal alpha-intercalated cell](/details-cell/CL0005011) and [kidney connecting tubule epithelial cell](/details-cell/CL1000768) likely reflects the energetic cost of active transport and pH regulation in the nephron. This broad but distinct expression landscape underscores the fundamental requirement for TMLHE-mediated carnitine synthesis in diverse, specialized cell types. ## Pathways and Molecular Function Functionally, [TMLHE](/details-gene/55217) is annotated as the enzyme responsible for trimethyllysine dioxygenase activity ([GO:0050353](https://www.ebi.ac.uk/QuickGO/term/GO:0050353)), a process requiring iron as a cofactor, as reflected by its iron ion binding capability ([GO:0005506](https://www.ebi.ac.uk/QuickGO/term/GO:0005506)). This enzymatic activity is the initial and rate-limiting step in the Carnitine biosynthetic process ([GO:0045329](https://www.ebi.ac.uk/QuickGO/term/GO:0045329)). Its involvement is well-defined within the Carnitine synthesis pathway ([R-HSA-71262](https://reactome.org/content/detail/R-HSA-71262)), a sub-pathway of the broader Metabolism of amino acids and derivatives ([R-HSA-71291](https://reactome.org/content/detail/R-HSA-71291)). The protein product is localized to the mitochondrial matrix ([GO:0005759](https://www.ebi.ac.uk/QuickGO/term/GO:0005759)), which is the site of fatty acid beta-oxidation. By producing carnitine, [TMLHE](/details-gene/55217) directly enables the transport of fatty acids across the inner mitochondrial membrane, providing a crucial substrate for ATP production. This function explains its high expression in energetically demanding cells like neurons and macrophages, which rely on efficient energy generation to maintain their complex functions. Research has confirmed its role in catalyzing the formation of (2S,3S)-3-hydroxy-Nepsilon-trimethyllysine, a key intermediate in the biosynthetic pathway [Link](https://doi.org/10.1039/c6cc08381a). ## Research Directions The association of [TMLHE](/details-gene/55217) loss-of-function with neurodevelopmental disorders, specifically autism spectrum disorders (ASDs), provides a compelling avenue for investigation [Link](https://doi.org/10.1093/hmg/ddr363), [Link](https://doi.org/10.1038/tp.2012.102). The gene's significant expression in [astrocytes](/details-cell/CL0002605) and [neurons](/details-cell/CL4023041) suggests that metabolic insufficiencies originating in these cells could contribute to the pathology. **Proposed Hypotheses:** 1. Loss-of-function mutations in [TMLHE](/details-gene/55217) lead to a carnitine deficiency in developing [neurons](/details-cell/CL4023041) and [astrocytes](/details-cell/CL0002605), impairing mitochondrial fatty acid oxidation. This bioenergetic deficit disrupts critical developmental processes such as synaptogenesis, dendritic arborization, and myelination, thereby contributing to the neurological phenotypes observed in ASD. 2. In the immune system, the high significance of [TMLHE](/details-gene/55217) in [alveolar macrophages](/details-cell/CL0000583) suggests that carnitine-dependent metabolism is essential for their function. It is hypothesized that reduced [TMLHE](/details-gene/55217) activity compromises the ability of these macrophages to mount an effective phagocytic or inflammatory response by limiting the ATP supply required for these high-energy processes. **Experimental Approach:** To test the first hypothesis, an *in vitro* model using human induced pluripotent stem cells (iPSCs) from individuals with known [TMLHE](/details-gene/55217) deletions and isogenic controls could be employed. These iPSCs would be differentiated into cortical neurons and astrocytes. Subsequent analysis using a Seahorse XF Analyzer would directly assess mitochondrial respiration and fatty acid oxidation capacity. Furthermore, immunofluorescence staining for synaptic markers (e.g., PSD-95, Synapsin I) and morphological analysis of neuronal complexity could quantify the impact of impaired carnitine synthesis on neuronal development. **Therapeutic Potential:** Given that [TMLHE](/details-gene/55217) mutations lead to a metabolic deficiency, it is not a candidate for inhibition. Instead, a metabolic rescue strategy is plausible. For individuals with confirmed loss-of-function variants, dietary supplementation with L-carnitine could bypass the enzymatic defect by providing the necessary molecule for fatty acid transport. This approach represents a potential low-risk therapeutic intervention aimed at restoring mitochondrial energy homeostasis, particularly in the central nervous system, and may warrant investigation in clinical studies for related neurodevelopmental disorders.

Genular Protein ID: 3303148111

Symbol: TMLH_HUMAN

Name: Trimethyllysine dioxygenase, mitochondrial

UniProtKB Accession Codes:

Q9NVH6 A8K6M9 B4E3R3 Q5TZB5 Q6IA90 Q8TBT0

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ChEBI 11 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 EC 1 EMBL 9 Ensembl 3 GO 6 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 8 Pumba 1 RNAct 1 Reactome 1 RefSeq 2 Rhea 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 11431483

Title: Molecular and biochemical characterization of rat epsilon-N-trimethyllysine hydroxylase, the first enzyme of carnitine biosynthesis.

PubMed ID: 11431483

DOI: 10.1074/jbc.m105929200

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15772651

Title: The DNA sequence of the human X chromosome.

PubMed ID: 15772651

DOI: 10.1038/nature03440

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: 15754339

Title: Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting.

PubMed ID: 15754339

DOI: 10.1002/jcp.20332

PubMed ID: 17408883

Title: Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants.

PubMed ID: 17408883

DOI: 10.1016/j.gene.2007.02.012

PubMed ID: 19608861

Title: Lysine acetylation targets protein complexes and co-regulates major cellular functions.

PubMed ID: 19608861

DOI: 10.1126/science.1175371

PubMed ID: 21865298

Title: Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.

PubMed ID: 21865298

DOI: 10.1093/hmg/ddr363

PubMed ID: 27965989

Title: Human carnitine biosynthesis proceeds via (2S,3S)-3-hydroxy-Nepsilon-trimethyllysine.

PubMed ID: 27965989

DOI: 10.1039/c6cc08381a

PubMed ID: 28045275

Title: Evidence that trimethyllysine hydroxylase catalyzes the formation of (2S,3S)-3-hydroxy-Nepsilon-trimethyllysine.

PubMed ID: 28045275

DOI: 10.1021/acs.orglett.6b03608

PubMed ID: 23092983

Title: Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.

PubMed ID: 23092983

DOI: 10.1038/tp.2012.102

Sequence Information:

  • Length: 421
  • Mass: 49518
  • Checksum: 4E55DF349B866B43
  • Sequence:
    • MWYHRLSHLH SRLQDLLKGG VIYPALPQPN FKSLLPLAVH WHHTASKSLT CAWQQHEDHF 
ELKYANTVMR FDYVWLRDHC RSASCYNSKT HQRSLDTASV DLCIKPKTIR LDETTLFFTW 
PDGHVTKYDL NWLVKNSYEG QKQKVIQPRI LWNAEIYQQA QVPSVDCQSF LETNEGLKKF 
LQNFLLYGIA FVENVPPTQE HTEKLAERIS LIRETIYGRM WYFTSDFSRG DTAYTKLALD 
RHTDTTYFQE PCGIQVFHCL KHEGTGGRTL LVDGFYAAEQ VLQKAPEEFE LLSKVPLKHE 
YIEDVGECHN HMIGIGPVLN IYPWNKELYL IRYNNYDRAV INTVPYDVVH RWYTAHRTLT 
IELRRPENEF WVKLKPGRVL FIDNWRVLHG RECFTGYRQL CGCYLTRDDV LNTARLLGLQ 
A