HMBS Gene (Hydroxymethylbilane Synthase): Function, Mutations, and Associated Diseases
Comprehensive biomedical overview of the HMBS gene, including genomic context, expression, mutations, and clinical significance.
Gene Information Card
| Symbol | HMBS |
|---|---|
| Full Name | Hydroxymethylbilane synthase |
| Gene Type | Protein coding |
| Chromosomal Location | 11q23.3 |
| NCBI Gene ID | 3145 ncbi.nlm.nih.gov/gene/3145 |
| Ensembl ID | ENSG00000256269 |
| UniProt ID | P08397 |
| OMIM ID | 609806 |
| HGNC ID | 4982 |
| Aliases | PBGD; UPS; PORPHOBILINOGEN DEAMINASE |
Description
The HMBS gene encodes hydroxymethylbilane synthase (also known as porphobilinogen deaminase), a key enzyme in the heme biosynthesis pathway. It catalyzes the sequential condensation of four molecules of porphobilinogen to form hydroxymethylbilane, a linear tetrapyrrole precursor of uroporphyrinogen III. Mutations in HMBS cause acute intermittent porphyria (AIP), an autosomal dominant metabolic disorder characterized by neurovisceral attacks. The gene is expressed ubiquitously, with highest levels in liver and erythroid tissues.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Acute intermittent porphyria (AIP) | Loss-of-function mutations in HMBS lead to reduced hydroxymethylbilane synthase activity, causing accumulation of porphobilinogen and delta-aminolevulinic acid, which are neurotoxic. | ClinVar; OMIM |
| Hereditary coproporphyria (possible modifier) | Rare variants in HMBS may modify clinical expression of other porphyrias, but direct causal role is not established. | ClinVar; literature |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | ~20 | High |
| Erythroid cells (bone marrow) | ~15 | High |
| Kidney | ~10 | Medium |
| Brain | ~5 | Low |
| Heart | ~3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver) | ~25 | High expression; used for enzyme assays |
| K562 (erythroleukemia) | ~18 | Erythroid-specific isoform expression |
| HeLa (cervical) | ~8 | Moderate expression |
| A549 (lung) | ~6 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.517C>T (p.Arg173Trp) | Missense | ~5% of AIP cases | Reduced enzyme activity; protein instability |
| c.652C>T (p.Arg218Trp) | Missense | ~3% of AIP cases | Impaired catalytic function |
| c.1073delA (p.Lys358Serfs*23) | Frameshift | ~2% of AIP cases | Truncated protein; loss of function |
| c.88G>A (p.Gly30Arg) | Missense | ~1% of AIP cases | Decreased enzyme activity |
Mutation functional classification
Loss of Function (LOF)
Most HMBS mutations are loss-of-function, leading to reduced or absent enzyme activity. This is the primary mechanism for acute intermittent porphyria.
Gain of Function (GOF)
No gain-of-function mutations have been reported for HMBS.
Dominant Negative (DN)
Some missense mutations may exert a dominant-negative effect by producing a defective enzyme that interferes with the normal tetrameric assembly, but this is not well established.
View complete mutation data：
Gene Ontology (GO)
| • hydroxymethylbilane synthase activity (GO:0004418) | • protoporphyrinogen IX biosynthetic process (GO:0006782) |
| • cytosol (GO:0005829) | • mitochondrion (indirectly via heme pathway) (GO:0005739) |
Pathways
• Heme biosynthesis (KEGG: hsa00860)
• Porphyrin metabolism (Reactome: R-HSA-189451)
Protein Summary
Hydroxymethylbilane synthase (HMBS) is a cytosolic enzyme composed of 361 amino acids (monomer) that functions as a homotetramer. It catalyzes the head-to-tail condensation of four porphobilinogen molecules to form the linear tetrapyrrole hydroxymethylbilane. The enzyme requires no cofactors but is sensitive to inhibition by its product. Alternative splicing produces two isoforms: a housekeeping form (ubiquitous) and an erythroid-specific form (lacking exon 1). Mutations affecting the housekeeping isoform are associated with AIP, while erythroid-specific mutations may cause milder phenotypes.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HMBS Knockout HEK293 Cell Line | EDJ-KQ4883 | Human | 3145 | Details Get a Quote |
| HMBS Knockout A-549 Cell Line | EDJ-KQ27683 | Human | 3145 | Details Get a Quote |
| HMBS Knockout HCT 116 Cell Line | EDJ-KQ27684 | Human | 3145 | Details Get a Quote |
| HMBS Knockout HeLa Cell Line | EDJ-KQ27685 | Human | 3145 | Details Get a Quote |
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