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    TMLHE trimethyllysine hydroxylase, epsilon [ Homo sapiens (human) ]

    Gene ID: 55217, updated on 10-Dec-2024

    Summary

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    Official Symbol
    TMLHEprovided by HGNC
    Official Full Name
    trimethyllysine hydroxylase, epsilonprovided by HGNC
    Primary source
    HGNC:HGNC:18308
    See related
    Ensembl:ENSG00000185973 MIM:300777; AllianceGenome:HGNC:18308
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    TMLD; TMLH; BBOX2; AUTSX6; TMLHED; XAP130
    Summary
    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]
    Expression
    Ubiquitous expression in heart (RPKM 6.4), fat (RPKM 5.3) and 25 other tissues See more
    Orthologs
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    Genomic context

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    See TMLHE in Genome Data Viewer
    Location:
    Xq28
    Exon count:
    13
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) X NC_000023.11 (155489011..155612952, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) X NC_060947.1 (153718334..153838175, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) X NC_000023.10 (154718672..154842613, complement)

    Chromosome X - NC_000023.11Genomic Context describing neighboring genes Neighboring gene int22h-3 recombination region Neighboring gene microRNA 1184-3 Neighboring gene TMLHE antisense RNA 1 Neighboring gene H2A.B variant histone 3 Neighboring gene coagulation factor VIII associated 3 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 30078 Neighboring gene sprouty RTK signaling antagonist 3 Neighboring gene meiotic recombination hotspot PAR2A Neighboring gene meiotic recombination hotspot PAR2 Neighboring gene adenosylmethionine decarboxylase 1 pseudogene 2 Neighboring gene diphthamide biosynthesis 3 pseudogene 2

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. Celestino-Soper PB, et al. Hum Mol Genet, 2011 Nov 15. PMID 21865298, Free PMC Article
    2. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Celestino-Soper PB, et al. Proc Natl Acad Sci U S A, 2012 May 22. PMID 22566635, Free PMC Article
    3. Investigating the active site of human trimethyllysine hydroxylase. Wang Y, et al. Biochem J, 2019 Apr 10. PMID 30898847
    4. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Nava C, et al. Transl Psychiatry, 2012 Oct 23. PMID 23092983, Free PMC Article
    5. Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants. Monfregola J, et al. Gene, 2007 Jun 15. PMID 17408883

    See all (36) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. This work demonstrates the importance of the recognition sites that contribute to the enzymatic activity of TMLH: the Fe(II)-binding H242-D244-H389 residues, R391-R398 involved in 2OG binding and several residues (D231, N334 and the aromatic cage comprised of W221, Y217 and Y234) associated with binding of (2S)-N (epsilon)-trimethyllysine.
      Title: Investigating the active site of human trimethyllysine hydroxylase.
    2. Case Report: complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis in proband's mother.
      Title: Complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis.
    3. Study found 3 mutations in TMLHE to be associated with autism spectrum disorder, c.229C>T/p.Arg77X, c.730G>C/p.Asp244His, and c.1107G>T/p.Glu369Asp.
      Title: Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
    4. TMLHE deficiency is common in control males and was not significantly increased in frequency in probands from simplex autism families, however, it was 2.82-fold more frequent in probands from male-male multiplex autism families.
      Title: A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.
    5. Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.
      Title: Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.
    6. By 5' and 3' RACE, we identified and mapped two alternative 5' TMLH first exons and seven alternative 3'-splice variants.
      Title: Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants.
    7. C-terminal region of trimethyllysine hydroxylase, epsilon contains the main determinants for its enzymatic activity including a key H389 residue
      Title: Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting.
    Submit: New GeneRIF Correction

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Epsilon-trimethyllysine hydroxylase deficiency
    MedGen: C3550875 OMIM: 300872 GeneReviews: Not available
    		Compare labs

    Copy number response

    Description
    Copy number response
    Triplosensitivity

    No evidence available (Last evaluated 2013-08-01)

    ClinGen Genome Curation Page
    Haploinsufficency

    Little evidence for dosage pathogenicity (Last evaluated 2013-08-01)

    ClinGen Genome Curation PagePubMed

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ10727

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables iron ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables trimethyllysine dioxygenase activity EXP
    Inferred from Experiment
    more info
    		 PubMed 
    NOT enables trimethyllysine dioxygenase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables trimethyllysine dioxygenase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables trimethyllysine dioxygenase activity IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in carnitine biosynthetic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in carnitine biosynthetic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in carnitine biosynthetic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in carnitine biosynthetic process IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in carnitine biosynthetic process TAS
    Traceable Author Statement
    more info
    		  
    involved_in negative regulation of oxidoreductase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in mitochondrial matrix TAS
    Traceable Author Statement
    more info
    		  
    located_in mitochondrion HTP PubMed 
    is_active_in mitochondrion IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in mitochondrion IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    trimethyllysine dioxygenase, mitochondrial
    Names
    TML hydroxylase
    TML-alpha-ketoglutarate dioxygenase
    butyrobetaine (gamma), 2-oxoglutarate dioxygenase (gamma-butyrobetaine hydroxylase) 2
    epsilon-trimethyllysine 2-oxoglutarate dioxygenase
    epsilon-trimethyllysine hydroxylase
    NP_001171726.1
    NP_060666.1
    XP_011529484.1
    XP_016885109.1
    XP_047298190.1
    XP_047298191.1
    XP_047298192.1
    XP_054183321.1
    XP_054183322.1
    XP_054183323.1
    XP_054183324.1
    XP_054183325.1

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_021318.1 RefSeqGene

      Range
      5010..128951
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001184797.2 → NP_001171726.1  trimethyllysine dioxygenase, mitochondrial isoform 2 precursor

      See identical proteins and their annotated locations for NP_001171726.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) differs in the 3' UTR and coding region differences, compared to variant 1. The resulting protein (isoform 2) has a distinct C-terminus and is shorter than isoform 1.
      Source sequence(s)
      BC025269, DA323339, DB174485
      Consensus CDS
      CCDS55547.1
      UniProtKB/Swiss-Prot
      Q9NVH6
      Related
      ENSP00000358447.4, ENST00000369439.4
      Conserved Domains (1) summary
      cl26676
      Location:70 → 332
      TauD; Taurine dioxygenase, alpha-ketoglutarate-dependent [Secondary metabolites biosynthesis, transport and catabolism]

    2. NM_018196.4 → NP_060666.1  trimethyllysine dioxygenase, mitochondrial isoform 1 precursor

      See identical proteins and their annotated locations for NP_060666.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AK001589, BX571846, DB174485
      Consensus CDS
      CCDS14768.1
      UniProtKB/Swiss-Prot
      A8K6M9, B4E3R3, Q5TZB5, Q6IA90, Q8TBT0, Q9NVH6
      Related
      ENSP00000335261.3, ENST00000334398.8
      Conserved Domains (1) summary
      TIGR02410
      Location:70 → 419
      carnitine_TMLD; trimethyllysine dioxygenase

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000023.11 Reference GRCh38.p14 Primary Assembly

      Range
      155489011..155612952 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047442235.1 → XP_047298191.1  trimethyllysine dioxygenase, mitochondrial isoform X2

    2. XM_047442234.1 → XP_047298190.1  trimethyllysine dioxygenase, mitochondrial isoform X1

    3. XM_011531182.4 → XP_011529484.1  trimethyllysine dioxygenase, mitochondrial isoform X1

      Conserved Domains (3) summary
      cd00250
      Location:91 → 357
      CAS_like; Clavaminic acid synthetase (CAS) -like; CAS is a trifunctional Fe(II)/ 2-oxoglutarate (2OG) oxygenase carrying out three reactions in the biosynthesis of clavulanic acid, an inhibitor of class A serine beta-lactamases. In general, Fe(II)-2OG oxygenases ...
      TIGR02410
      Location:19 → 368
      carnitine_TMLD; trimethyllysine dioxygenase
      cl01414
      Location:10 → 82
      DUF971; Protein of unknown function (DUF971)

    4. XM_047442236.1 → XP_047298192.1  trimethyllysine dioxygenase, mitochondrial isoform X2

    5. XM_017029620.3 → XP_016885109.1  trimethyllysine dioxygenase, mitochondrial isoform X3

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060947.1 Alternate T2T-CHM13v2.0

      Range
      153718334..153838175 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054327348.1 → XP_054183323.1  trimethyllysine dioxygenase, mitochondrial isoform X2

    2. XM_054327346.1 → XP_054183321.1  trimethyllysine dioxygenase, mitochondrial isoform X4

      UniProtKB/Swiss-Prot
      A8K6M9, B4E3R3, Q5TZB5, Q6IA90, Q8TBT0, Q9NVH6

    3. XM_054327347.1 → XP_054183322.1  trimethyllysine dioxygenase, mitochondrial isoform X1

    4. XM_054327349.1 → XP_054183324.1  trimethyllysine dioxygenase, mitochondrial isoform X2

    5. XM_054327350.1 → XP_054183325.1  trimethyllysine dioxygenase, mitochondrial isoform X3

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9NVH6.1 GenPept UniProtKB/Swiss-Prot:Q9NVH6

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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