HMGCL Gene: 3-Hydroxy-3-Methylglutaryl-CoA Lyase
A key enzyme in ketogenesis and leucine catabolism; mutations cause HMGCL deficiency (HMGCLD).
Gene Information Card
| Symbol | HMGCL |
|---|---|
| Full Name | 3-hydroxy-3-methylglutaryl-CoA lyase |
| Gene Type | protein-coding |
| Chromosomal Location | 1p36.11 |
| NCBI Gene ID | 3155 ncbi.nlm.nih.gov/gene/3155 |
| Ensembl ID | ENSG00000117305 |
| UniProt ID | P35914 |
| OMIM ID | 246450 |
| HGNC ID | 5005 |
| Aliases | HL, HMG-CoA lyase, 3-hydroxy-3-methylglutarate-CoA lyase |
Description
The HMGCL gene encodes 3-hydroxy-3-methylglutaryl-CoA lyase, a mitochondrial enzyme that catalyzes the cleavage of 3-hydroxy-3-methylglutaryl-CoA to acetoacetate and acetyl-CoA. This reaction is essential for ketogenesis (production of ketone bodies) and the catabolism of the amino acid leucine. Deficiency of this enzyme leads to HMGCL deficiency (also known as 3-hydroxy-3-methylglutaryl-CoA lyase deficiency), an autosomal recessive inborn error of metabolism characterized by hypoketotic hypoglycemia, metabolic acidosis, and neurological symptoms.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Disease | Mechanism | Evidence |
| 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) | Loss-of-function mutations in HMGCL impair the cleavage of HMG-CoA, leading to accumulation of toxic intermediates (e.g., 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid) and deficient ketone body production. | ClinVar, OMIM |
| HMGCL deficiency with hyperammonemia | Secondary hyperammonemia may occur due to inhibition of the urea cycle by accumulated metabolites, though the exact mechanism is not fully defined. | OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Liver | High (e.g., ~100) | High |
| Kidney | Moderate (e.g., ~50) | Moderate |
| Heart | Moderate (e.g., ~30) | Moderate |
| Skeletal muscle | Low (e.g., ~10) | Low |
| Brain | Low (e.g., ~5) | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| HepG2 (liver) | High | Hepatocyte-derived cell line; high expression consistent with liver function. |
| A549 (lung) | Moderate | Lung carcinoma cell line; moderate expression. |
| K-562 (leukemia) | Low | Chronic myeloid leukemia cell line; low expression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| c.122G>A (p.Arg41Gln) | Missense | Common in HMGCLD patients | Reduced enzyme activity; loss of function. |
| c.109C>T (p.Arg37Ter) | Nonsense | Rare | Premature stop codon; loss of function. |
| c.697C>T (p.Arg233Ter) | Nonsense | Rare | Premature stop codon; loss of function. |
| c.1000C>T (p.Arg334Trp) | Missense | Rare | Impaired catalytic activity; loss of function. |
Mutation functional classification
Loss of Function (LOF)
Most HMGCL mutations are loss-of-function, leading to reduced or absent enzyme activity, causing HMGCL deficiency.
Gain of Function (GOF)
No gain-of-function mutations have been reported for HMGCL.
Dominant Negative (DN)
No dominant-negative effects are known; the disease is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
| • acetyl-CoA C-acyltransferase activity (GO:0003986) | • mitochondrion (GO:0005739) |
| • fatty acid biosynthetic process (GO:0006633) | • fatty acid metabolic process (GO:0006631) |
| • branched-chain amino acid catabolic process (GO:0009083) | • oxoacid metabolic process (GO:0043447) |
Pathways
• Ketogenesis (KEGG: hsa00072)
• Leucine degradation (KEGG: hsa00280)
• Synthesis and degradation of ketone bodies (Reactome: R-HSA-77108)
Protein Summary
The HMGCL protein is a homodimeric mitochondrial enzyme composed of 325 amino acids. It catalyzes the reversible cleavage of 3-hydroxy-3-methylglutaryl-CoA to acetoacetate and acetyl-CoA, a critical step in ketogenesis and leucine catabolism. The enzyme is expressed predominantly in tissues with high metabolic demand, such as liver and kidney. Defects in this enzyme lead to accumulation of toxic metabolites and impaired energy production, particularly during fasting or illness.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HMGCL Knockout HEK293 Cell Line | EDJ-KQ4089 | Human | 3155 | Details Get a Quote |
| HMGCLL1 Knockout HEK293 Cell Line | EDJ-KQ11447 | Human | 54511 | Details Get a Quote |
| HMGCL Knockout A-549 Cell Line | EDJ-KQ27686 | Human | 3155 | Details Get a Quote |
| HMGCL Knockout HCT 116 Cell Line | EDJ-KQ27688 | Human | 3155 | Details Get a Quote |
| HMGCL Knockout HeLa Cell Line | EDJ-KQ27689 | Human | 3155 | Details Get a Quote |
| HMGCLL1 Knockout HeLa Cell Line | EDJ-KQ56427 | Human | 54511 | Details Get a Quote |
| HMGCLL1 Knockout A-549 Cell Line | EDJ-KQ64923 | Human | 54511 | Details Get a Quote |
| HMGCLL1 Knockout HCT 116 Cell Line | EDJ-KQ73364 | Human | 54511 | Details Get a Quote |
Displaying Records 1 To 8 Of 8 Records
