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TNFRSF6

MIM.134637 10q24.1

Thursday 27 January 2005

FAS(CD95) is a proapoptotic protein expressed within GCs where it plays an important role in negative selection of B cells.

FAS ligand cross-links the transmembrane FAS death receptor, leading to the assembly of a death-inducing signaling complex and initiating caspase-mediated apoptosis.

Pathology

- germline mutations of FAS in autosomal recessive autoimmune lymphoproliferative syndrome type 1A (ALPS1A) (MIM.601859)

- somatic mutation of FAS in burn scar-related cutaneous squamous cell carcinoma

- somatic mutation of FAS in diffuse large B-cell lymphoma (DLBCL)

  • FAS mutations have been reported in up to about 20% of DLBCLs, most commonly within the last exon, which encodes the death domain.
  • Such mutations likely act in a dominant-negative manner, destabilizing trimeric FAS receptors.
  • Loss of FAS leads to defective affinity maturation and failure to negatively select autoreactive B cells, which may lead to autoimmune disease and persistence of malignant clones.

Animal model

- Mice with FAS and FAS ligand (FAS-L) mutations are prone to development of B-cell lymphomas, as are families with germline FAS mutations and associated autoimmune lymphoproliferative syndrome (ALPS).

- Fas-mediated fulminant hepatitis in mice (TNFRSF6)

References

- Abramson JS, Shipp MA. Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood. 2005 Aug 15;106(4):1164-74. PMID: 15855278

- Wallach D, et al: Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 17:331, 1999.