Autoimmune lymphoproliferative syndrome 1A

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Wikipedia on Autoimmune lymphoproliferative syndrome 1A (Less technical, ? quality control)

The FAS gene at 10q23.31 codes for the 335 amino acid peptide Tumour necrosis factor receptor superfamily member 6. This is the receptor for tumor necrosis factor ligand superfamily member 6 (CD178, FAS-L) that transduces the apoptotic signal into cells. The adapter molecule FAS-associated death domain protein recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases mediating apoptosis. Seven isoforms are produced by alternative splicing of which all but isoform 1 inhibit apoptosis. These include the commonest FasExo8Del isoform as well as del2 (D), del3 (E), B, C, and TMdel (A) isoforms. Tumour necrosis factor receptor superfamily member 6 mediated apoptosis plays a critical role in eliminating the unwanted activation of B-cells by self-reactive antigens and in maintaining B-cell homoeostasis through activation-induced B-cell death. FAS signaling is important in oncology[1] and modulated by agents such as sorafenib (promotes receptor tyrosine phosphorylation) and vorinostat (facilitation of reactive oxygen species generation and subsequently of FAS-ligand expression) used to treat some cancers[2].

Naturally occurring anti-FAS immunoglobulin is present in intravenous immunoglobulin (IVIG) and by blocking the FAS receptor the response to treatment in conditions such as toxic epidermal necrolysis is explained. The FAS receptor has been shown to have a growth-promoting role during tumourigenesis. Tumour necrosis factor receptor superfamily member 6 binds death domain-associated protein 6, receptor-interacting serine/threonine-protein kinase 1 and protein lifeguard 2. It interacts with homeodomain-interacting protein kinase 3, FAS-associated death domain protein, BRCA1-A complex subunit BRE and protein fem-1 homolog B.

Mutations of FAS cause autoimmune lymphoproliferative syndrome 1A (ALPS1A, OMIM:601859) which from early childhood presents with non-malignant lymphadenopathy, hepatosplenomegaly, autoimmune haemolytic anaemia, thrombocytopenia and neutropenia due to autoreactive lymphocytes causing blood line component apoptosis. There is also an association of gene variants with scar cancers and SLE[3]. Indeed FAS was the first described autogene[4].