LRRC8A: The Volume-Regulated Anion Channel Subunit and Its Role in Human Disease
A comprehensive biomedical overview of LRRC8A, a key component of the VRAC channel, including its genomic context, expression, mutations, and clinical significance.
Gene Information Card
| Symbol | LRRC8A |
|---|---|
| Full Name | Leucine Rich Repeat Containing 8 VRAC Subunit A |
| Gene Type | protein coding |
| Chromosomal Location | 9q34.11 |
| NCBI Gene ID | 56262 ncbi.nlm.nih.gov/gene/56262 |
| Ensembl ID | ENSG00000136859 |
| UniProt ID | Q8IWT6 |
| OMIM ID | 608360 |
| HGNC ID | 19027 |
| Aliases | SWELL1, LRRC8, AGM5 |
Description
LRRC8A encodes a leucine-rich repeat-containing protein that is an essential subunit of the volume-regulated anion channel (VRAC). VRAC is activated by cell swelling and mediates the efflux of chloride and organic osmolytes, playing a critical role in cell volume regulation. LRRC8A is also involved in other cellular processes, including apoptosis, cell proliferation, and immune responses. Mutations in LRRC8A have been linked to agammaglobulinemia type 5 and certain cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Agammaglobulinemia 5 (AGM5) | Loss-of-function mutations in LRRC8A impair VRAC activity, leading to defective B-cell development and antibody production. | ClinVar; OMIM (608360) |
| Colorectal cancer | LRRC8A expression is upregulated in colorectal cancer tissues, potentially promoting tumor growth and metastasis through enhanced VRAC activity. | COSMIC; PubMed (multiple studies) |
| Glioblastoma | LRRC8A is overexpressed in glioblastoma and contributes to cell proliferation and invasion, possibly via VRAC-mediated signaling. | COSMIC; PubMed |
| Hepatocellular carcinoma | LRRC8A expression is elevated in liver cancer and may support tumor progression by regulating cell volume and apoptosis resistance. | COSMIC; PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 44.2 | High |
| Lymph node | 38.5 | High |
| Spleen | 35.1 | High |
| Bone marrow | 30.8 | Medium |
| Lung | 25.4 | Medium |
| Liver | 22.3 | Medium |
| Brain | 18.7 | Low |
| Heart | 15.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 32.5 | High expression; commonly used for VRAC studies |
| HeLa | 28.9 | Moderate expression; used in cancer research |
| A549 | 26.3 | Lung carcinoma; moderate expression |
| MCF7 | 24.1 | Breast cancer; moderate expression |
| K562 | 22.8 | Leukemia; moderate expression |
| HepG2 | 20.5 | Liver cancer; moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Arg98* | Nonsense | Rare | Loss of function; causes agammaglobulinemia |
| p.Leu107Phe | Missense | Rare | Loss of function; associated with agammaglobulinemia |
| p.Arg313His | Missense | Somatic (cancer) | Potential gain of function; observed in colorectal cancer |
| p.Gly355Asp | Missense | Somatic (cancer) | Unknown; found in glioblastoma |
Mutation functional classification
Loss of Function (LOF)
Nonsense and missense mutations that impair VRAC channel activity, leading to defective B-cell development and agammaglobulinemia.
Gain of Function (GOF)
Somatic missense mutations in cancers may enhance VRAC activity, promoting cell proliferation and survival.
Dominant Negative (DN)
Some mutations may exert dominant-negative effects by disrupting the heteromeric assembly of VRAC subunits.
View complete mutation data：
Gene Ontology (GO)
| • volume-regulated anion channel activity | • chloride channel activity |
| • protein binding | • plasma membrane |
| • integral component of membrane | • cell volume homeostasis |
| • response to osmotic stress | • apoptotic process |
| • B cell differentiation |
Pathways
• Volume-regulated anion channel (VRAC) pathway
• Ion transport
• Cell volume regulation
• B cell receptor signaling (indirect)
Protein Summary
The LRRC8A protein is a 810-amino acid transmembrane protein with four N-terminal transmembrane domains and a C-terminal leucine-rich repeat (LRR) domain. It forms heterohexameric complexes with other LRRC8 family members (LRRC8B-E) to constitute the VRAC channel. LRRC8A is essential for VRAC function; without it, the channel is non-functional. The protein is ubiquitously expressed but shows higher levels in immune tissues. It plays a role in cell volume regulation, apoptosis, and immune responses. Mutations can lead to primary immunodeficiency or contribute to cancer progression.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| LRRC8A Knockout HEK293 Cell Line | EDJ-KQ3564 | Human | 56262 | Details Get a Quote |
| LRRC8A Knockout HeLa Cell Line | EDJ-KQ24056 | Human | 56262 | Details Get a Quote |
| LRRC8A Knockout A-549 Cell Line | EDJ-KQ25431 | Human | 56262 | Details Get a Quote |
| LRRC8A Knockout HCT 116 Cell Line | EDJ-KQ25432 | Human | 56262 | Details Get a Quote |
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