Alt. symbols: TWEAK | DR3LG | APO3L

Approved name: TNF superfamily member 12
Alt. names: tumor necrosis factor (ligand) superfamily, member 12

Location: 17p13.1: 7548508 - 7557890 (+)
Gene type: protein_coding, 20 transcripts.

Scores: LoFtool: 0.174000 | pLI: 0.99795402 | LOEUF: 0.408

HGNC: 11927

NCBI: 8742, RefSeq: NG_052944.1

Ensembl: ENSG00000239697.12

LRG_1320 | Status: public

OMIM: 602695

Expression | ProteinAtlas

TNFSF12 encodes TWEAK, a ligand whose exact functions remain unclear but may work in complex with related ligands to promote apoptosis during B-cell development and selection (PMID: 9405449). Like other TNFSF ligands, TWEAK can function as a secreted or transmembrane protein (PMID: 20385556) and is widely expressed across many tissues and cell types, including monocytes/macrophages, DCs, NK cells, and T cells. It is upregulated in inflammation, and has been shown to negatively regulate innate immune activation of adaptive Th1 immunity through its receptor (PMID: 16325585).

By screening PAD patients with a custom 148 gene-based resequencing chip, Wang et al. (2013) identified a rare heterozygous missense mutation in a patient with impaired antibody responses, reduced IgM and IgA levels, and expanded TCRα/β+ double negative T cells (PMID: 23493554). The authors showed that this mutation did not affect TWEAK binding to its receptor (if anything slightly increased), but did impair its ability to induce apoptosis via reduced activation of NF-κB and mitog en-activated protein kinase (MAPK) pathways. Further, mutant TWEAK also showed stronger binding to BAFF, but not BAFF-R, and was found to impair downstream BAFF signaling, presumably via a DN effect such as the formation of ineffective ligand complexes. However, given some of the clinical differences between BAFF-R-deficient patients and the TWEAK patient, as well as the significant crosstalk and interactions across multiple TNFSF receptors, it is likely that altered interactions with other ligands or receptors, such as APRIL or TACI, may also contribute to the latter’s phenotype. [Load More]