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The CASP8 gene at 2q33.1 codes for the 479 amino acid pro-peptide to caspase-8. Association with FAS-associated death domain protein results in the formation of the death-inducing signaling complex (DISC) where it is activated by being cleaved into:

  1. Caspase-8 subunit p18
  2. Caspase-8 subunit p10

Association with both receptor-interacting serine/threonine-protein kinase 1 and FAS-associated death domain protein forms an even larger complex called the ripoptosome which mediates programmed necroptosis. Caspase-8 deficiency (autoimmune lymphoproliferative syndrome type IIB, OMIM:607271) is manifest by:

  • Lymphadenopathy and splenomegaly
  • Marginal elevation of double-negative T cells (DNT; T-cell receptor alpha/beta+, CD4-/CD8-)
  • Defective FAS-induced apoptosis
  • Defective T-cell, B-cell, and NK-cell activation, with recurrent bacterial and viral infections