UNC13D Gene: Key Regulator of Cytotoxic Granule Exocytosis
UNC13D (unc-13 homolog D) is essential for immune cell cytotoxicity; mutations cause familial hemophagocytic lymphohistiocytosis type 3 (FHL3).
Gene Information Card
| Symbol | UNC13D |
|---|---|
| Full Name | unc-13 homolog D |
| Gene Type | protein-coding |
| Chromosomal Location | 17q25.1 |
| NCBI Gene ID | 201627 ncbi.nlm.nih.gov/gene/201627 |
| Ensembl ID | ENSG00000192929 |
| UniProt ID | Q70J99 |
| OMIM ID | 608897 |
| HGNC ID | 23147 |
| Aliases | Munc13-4, FHL3, HLH3, MUNC13-4 |
Description
UNC13D encodes Munc13-4, a member of the UNC13 family of proteins that regulate vesicle priming and exocytosis. Munc13-4 is critical for the fusion of cytotoxic granules with the plasma membrane in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Loss-of-function mutations in UNC13D impair cytotoxic granule release, leading to familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a severe primary immunodeficiency characterized by uncontrolled immune activation and inflammation.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) | Loss-of-function mutations impair cytotoxic granule exocytosis, preventing target cell killing and leading to hyperinflammation. | OMIM #608898; ClinVar; NCBI Gene |
| Hemophagocytic lymphohistiocytosis (HLH) | UNC13D mutations cause defective NK/CTL cytotoxicity, a hallmark of HLH. | ClinVar; OMIM |
| Primary immunodeficiency with defective cytotoxic function | Reduced or absent Munc13-4 disrupts granule secretion, compromising immune surveillance. | NCBI Gene; UniProt |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Spleen | 12.5 | Medium |
| Lymph node | 10.2 | Medium |
| Bone marrow | 8.9 | Medium |
| Whole blood | 6.1 | Low |
| Lung | 4.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| NK-92 (NK cell line) | 15.8 | High expression; used in functional studies |
| Jurkat (T cell line) | 9.2 | Moderate expression |
| K562 (erythroleukemia) | 2.1 | Low expression |
| HEK293 (embryonic kidney) | 1.5 | Very low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.753+1G>T | Splice site | ~30% of FHL3 alleles | Loss of function; exon skipping, frameshift |
| c.2346_2349delGGAG | Frameshift deletion | ~10% of FHL3 alleles | Premature stop; truncated protein |
| c.2588G>A (p.Arg863Gln) | Missense | <5% | Impaired granule exocytosis |
| c.127C>T (p.Arg43*) | Nonsense | <5% | Loss of function; no protein |
Mutation functional classification
Loss of Function (LOF)
Most UNC13D mutations are loss-of-function, leading to absent or non-functional Munc13-4 protein, defective cytotoxic granule exocytosis, and FHL3.
Gain of Function (GOF)
No gain-of-function mutations reported in UNC13D.
Dominant Negative (DN)
No dominant-negative mutations reported; FHL3 is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Natural killer cell mediated cytotoxicity (KEGG hsa04650)
• Vesicle-mediated transport (Reactome R-HSA-5653656)
• Munc13-4-mediated granule exocytosis (Reactome R-HSA-2029485)
Protein Summary
Munc13-4 (UniProt Q70J99) is a 1090-amino acid protein containing C2 domains and a MUN domain, which mediate calcium-dependent phospholipid binding and SNARE complex assembly. It localizes to cytotoxic granules and the plasma membrane, facilitating vesicle priming and fusion. Defects in Munc13-4 disrupt the final step of granule exocytosis, leading to impaired killing of infected or malignant cells.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| UNC13D Knockout HEK293 Cell Line | EDJ-KQ3512 | Human | 201294 | Details Get a Quote |
| UNC13D Knockout A-549 Cell Line | EDJ-KQ25329 | Human | 201294 | Details Get a Quote |
| UNC13D Knockout HCT 116 Cell Line | EDJ-KQ25330 | Human | 201294 | Details Get a Quote |
| UNC13D Knockout HeLa Cell Line | EDJ-KQ25331 | Human | 201294 | Details Get a Quote |
