Mutations in apoptosis genes: a pathogenetic factor for human disease

Cell death by apoptosis is exerted by the coordinated action of many differ ent gene products. Mutations in some of them, acting at different levels in the apoptosis process, have been identified as cause or contributing facto r for human diseases. Defects in the transmembrane tumor necrosis factor re ceptor 1 (TNF-R1) lead to the development of familial periodic fever syndro mes. Mutations in the homologous receptor Fas (also named CD95; Apo-1) are observed in malignant lymphomas, solid tumors and the autoimmune lymphoprol iferative syndrome type I (ALPS I). A mutation in the ligand for Fas (Fas l igand; CD95 ligand, Apo-l ligand), which induces apoptosis upon binding to Fas, was described in a patient with systemic lupus erythematodes and lymph adenopathy. Perforin, an other cytotoxic protein employed by T- and NK-cell s for target cell killing, is mutated in chromosome 10 linked cases of fami lial hemophagocytic lymphohistiocytosis. Caspase 10, a representative of th e caspase family of proteases, which plays a central role in the execution of apoptosis, is defect in autoimmune lymphoproliferative syndrome type Il (ALPS LI). The intracellular pro-apoptotic molecule bcl-10 is frequently mu tated in mucosa-associated lymphoid tissue (MALT) lymphomas and various non -hematologic malignancies. The p53, an executioner of DNA damage triggered apoptosis, and Bar, a pro-apoptotic molecule with the ability to perturb mi tochondrial membrane integrity, are frequently mutated in malignant neoplas ms. Anti-apoptotic proteins like bcl-2, cellular-inhibitor of apoptosis pro tein 2 (c-IAP2) and neuronal apoptosis inhibitory protein 1 (NAIP1) are oft en altered in follicular lymphomas, MALT lymphomas and spinal muscular atro phy (SMA), respectively. This article reviews the current knowledge on muta tions of apoptosis genes involved in the pathogenesis of human diseases and summarises the gradual transformation of discoveries in apoptosis research into benefits for the clinical management of diseases. (C) 2001 Elsevier S cience B.V. All rights reserved.