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

Summary

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: mouse all
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Genomic context

Location:: 1p36.11

Exon count:: 9

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	1	NC_000001.11 (23801885..23825429, complement)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	1	NC_060925.1 (23636860..23660403, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	1	NC_000001.10 (24128375..24151919, complement)

Chromosome 1 - NC_000001.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

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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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

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.
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.
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.
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.
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.
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.
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.
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.
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.
An alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively, were detected.
Title: Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway.

Submit: New GeneRIF Correction See all GeneRIFs (24)

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	Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

GDB:636092 (e-PCR)
- UniSTS:158523

SHGC-12784 (e-PCR)
- UniSTS:52574

RH68992 (e-PCR)
- UniSTS:19563

D1S3295 (e-PCR)
- UniSTS:39577

AL033765 (e-PCR)
- UniSTS:93617

GDB:549168 (e-PCR)
- UniSTS:157620

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
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

EC 4.1.3.4

NP_001159531.1

EC 4.1.3.4

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

NG_013061.1 RefSeqGene

Range

5031..28575

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

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
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