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HMGCL 3-hydroxy-3-methylglutaryl-CoA lyase [ Homo sapiens (human) ]

Gene ID: 3155, updated on 3-Nov-2024

Summary

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Official Symbol
HMGCLprovided by HGNC
Official Full Name
3-hydroxy-3-methylglutaryl-CoA lyaseprovided by HGNC
Primary source
HGNC:HGNC:5005
See related
Ensembl:ENSG00000117305 MIM:613898; AllianceGenome:HGNC:5005
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
HL; HMGCL1
Summary
The protein encoded by this gene belongs to the HMG-CoA lyase family. It is a mitochondrial enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Mutations in this gene are associated with HMG-CoA lyase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]
Expression
Ubiquitous expression in liver (RPKM 67.1), kidney (RPKM 50.9) and 24 other tissues See more
Orthologs
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Genomic context

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See HMGCL in Genome Data Viewer
Location:
1p36.11
Exon count:
9
Annotation release Status Assembly Chr Location
RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 1 NC_000001.11 (23801885..23825429, complement)
RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 1 NC_060925.1 (23636860..23660403, complement)
RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 1 NC_000001.10 (24128375..24151919, complement)

Chromosome 1 - NC_000001.11Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC105376860 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 423 Neighboring gene lysophospholipase 2 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 424 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 425 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 426 Neighboring gene UDP-galactose-4-epimerase Neighboring gene ATAC-STARR-seq lymphoblastoid active region 377 Neighboring gene ReSE screen-validated silencer GRCh37_chr1:24137325-24137530 Neighboring gene H3K27ac hESC enhancer GRCh37_chr1:24151920-24152788 Neighboring gene uncharacterized LOC105376861 Neighboring gene alpha-L-fucosidase 1 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr1:24191742-24192941 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 427

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 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. Skipping of exon 2 and exons 2 plus 3 of HMG-CoA lyase (HL) gene produces the loss of beta sheets 1 and 2 in the recently proposed (beta-alpha)8 TIM barrel model of HL. Puisac B, et al. Biophys Chem, 2005 Apr 1. PMID 15752612
  2. Analysis of aberrant splicing and nonsense-mediated decay of the stop codon mutations c.109G>T and c.504_505delCT in 7 patients with HMG-CoA lyase deficiency. Puisac B, et al. Mol Genet Metab, 2013 Apr. PMID 23465862
  3. Measurement of HMG CoA reductase activity in different human cell lines by ultra-performance liquid chromatography tandem mass spectrometry. Kuzaj P, et al. Biochem Biophys Res Commun, 2014 Jan 10. PMID 24333427
  4. 3-HMG Coenzyme A Lyase Deficiency: Macrocephaly and Left Ventricular Noncompaction with a Novel Mutation. Köksal T, et al. Indian J Pediatr, 2015 Jul. PMID 25708061
  5. Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Aoyama Y, et al. Int J Mol Med, 2015 Jun. PMID 25872961, Free PMC Article

See all (72) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. miR-1202 regulates BPH-1 cell proliferation, apoptosis, and epithelial-to-mesenchymal transition through targeting HMGCL.
    Title: miR-1202 regulates BPH-1 cell proliferation, apoptosis, and epithelial-to-mesenchymal transition through targeting HMGCL.
  2. Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/beta-catenin pathway in glioblastoma.
    Title: Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/β-catenin pathway in glioblastoma.
  3. HMGCL-induced beta-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility.
    Title: HMGCL-induced β-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility.
  4. The expression of HMGCL was silenced in nasopharyngeal carcinoma tissue. Downregulation of HMGCL in nasopharyngeal carcinoma was associated with low intracellular beta-hydroxybutyrate (beta-HB) production, thereby reducing reactive oxygen species (ROS) generation.
    Title: Inactivation of HMGCL promotes proliferation and metastasis of nasopharyngeal carcinoma by suppressing oxidative stress.
  5. Data suggest that HMGCS1 (HMG-CoA synthase 1) signals through ketogenesis/acetoacetate to promote cell proliferation and BRAF(V600E)-dependent MEK1 activation in BRAF(V600E)-positive melanoma and colon cancer cells; HMGCS1 co-localizes with HMGCL (HMG-CoA lyase) and BRAF(V600E) in cytosol of melanoma and colon cancer cells. (BRAF = proto-oncogene protein B-raf)
    Title: HMG-CoA synthase 1 is a synthetic lethal partner of BRAF(V600E) in human cancers.
  6. The genetic analysis revealed a novel homozygote deletion in exon 3 and 4 in HMGCL gene. HMG-CoA lyase deficiency should be thought in the patients with hypoketotic hypoglycemia, hyperammonemia, elevated liver function tests, noncompaction left ventricle and characteristic white matter changes and in the differential diagnosis of macrocephaly.
    Title: 3-HMG Coenzyme A Lyase Deficiency: Macrocephaly and Left Ventricular Noncompaction with a Novel Mutation.
  7. this is the first study describing HMGCL deficiency caused by uniparental disomy.
    Title: Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
  8. This efficient UPLC-MS/MS assay permits rapid and high sensitive determination of HMGCR enzyme activity, tracing potential alterations in cholesterol biosynthesis.
    Title: Measurement of HMG CoA reductase activity in different human cell lines by ultra-performance liquid chromatography tandem mass spectrometry.
  9. in the 2 stop codon mutations c.109G>T and c.504_505delCT studied, the stop codon does not appear to be the cause of aberrant splicing; the mutation c.504_505delCT causes 2 mRNA transcripts with a stop codon that generate two simultaneous nonsense-mediated mRNA decay phenomena
    Title: Analysis of aberrant splicing and nonsense-mediated decay of the stop codon mutations c.109G>T and c.504_505delCT in 7 patients with HMG-CoA lyase deficiency.
  10. analysis of HMGCLL1 as an extramitochondrial human 3-hydroxy-3-methylglutaryl-CoA lyase and comparison with MHGCL
    Title: Identification and characterization of an extramitochondrial human 3-hydroxy-3-methylglutaryl-CoA lyase.
Submit: New GeneRIF Correction See all GeneRIFs (25)

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
Deficiency of hydroxymethylglutaryl-CoA lyase
MedGen: C0268601 OMIM: 246450 GeneReviews: Not available
not available

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

Potential readthrough

Included gene: GALE

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables hydroxymethylglutaryl-CoA lyase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables hydroxymethylglutaryl-CoA lyase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables magnesium ion binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables manganese ion binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables metal ion binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables structural molecule activity IDA
Inferred from Direct Assay
more info
 PubMed 
Process Evidence Code Pubs
involved_in L-leucine catabolic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in L-leucine catabolic process NAS
Non-traceable Author Statement
more info
 PubMed 
involved_in L-leucine catabolic process TAS
Traceable Author Statement
more info
 PubMed 
involved_in ketone body biosynthetic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in ketone body biosynthetic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in lipid metabolic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in mitochondrion organization IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
located_in cytosol TAS
Traceable Author Statement
more info
  
located_in mitochondrial matrix NAS
Non-traceable Author Statement
more info
 PubMed 
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 
located_in peroxisomal matrix TAS
Traceable Author Statement
more info
  
located_in peroxisome IDA
Inferred from Direct Assay
more info
 PubMed 
part_of protein-containing complex IDA
Inferred from Direct Assay
more info
 PubMed 

General protein information

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Preferred Names
hydroxymethylglutaryl-CoA lyase, mitochondrial
Names
3-hydroxy-3-methylglutarate-CoA lyase
3-hydroxymethyl-3-methylglutaryl-CoA lyase
3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase
HMG-CoA lyase
hydroxymethylglutaricaciduria
mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase
NP_000182.2
NP_001159531.1

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_013061.1 RefSeqGene

    Range
    5031..28575
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_000191.3 → NP_000182.2  hydroxymethylglutaryl-CoA lyase, mitochondrial isoform 1 precursor

    See identical proteins and their annotated locations for NP_000182.2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) encodes the longer isoform (1).
    Source sequence(s)
    AI202943, AL031295, AL590728
    Consensus CDS
    CCDS243.1
    UniProtKB/Swiss-Prot
    B4DUP4, B7UCC6, D3Y5K7, P35914, Q6IBC0, Q96FP8
    UniProtKB/TrEMBL
    A6NMQ0, B1AK13
    Related
    ENSP00000363614.3, ENST00000374490.8
    Conserved Domains (1) summary
    cd07938
    Location:35 → 308
    DRE_TIM_HMGL; 3-hydroxy-3-methylglutaryl-CoA lyase, catalytic TIM barrel domain

  2. NM_001166059.2 → NP_001159531.1  hydroxymethylglutaryl-CoA lyase, mitochondrial isoform 2 precursor

    See identical proteins and their annotated locations for NP_001159531.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant is missing two consecutive in-frame coding exons compared to variant 1, resulting in a shorter isoform (2) lacking an internal protein segment compared to isoform 1.
    Source sequence(s)
    BC010570, CA306929, DA425822, L07033
    Consensus CDS
    CCDS53279.1
    UniProtKB/Swiss-Prot
    P35914
    Related
    ENSP00000389281.2, ENST00000436439.6
    Conserved Domains (2) summary
    PLN02746
    Location:17 → 254
    PLN02746; hydroxymethylglutaryl-CoA lyase
    pfam00682
    Location:32 → 235
    HMGL-like; HMGL-like

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_000001.11 Reference GRCh38.p14 Primary Assembly

    Range
    23801885..23825429 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060925.1 Alternate T2T-CHM13v2.0

    Range
    23636860..23660403 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P35914.2 GenPept UniProtKB/Swiss-Prot:P35914

Gene LinkOut

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

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