title: Mutations in apoptosis genes: a pathogenetic factor for human disease.
abstract: Cell death by apoptosis is exerted by the coordinated action of many different gene products. Mutations in some of them, acting at different levels in the apoptosis process, have been identified as cause or contributing factor for human diseases. Defects in the transmembrane tumor necrosis factor receptor 1 (TNF-R1) lead to the development of familial periodic fever syndromes. Mutations in the homologous receptor Fas (also named CD95; Apo-1) are observed in malignant lymphomas, solid tumors and the autoimmune lymphoproliferative syndrome type I (ALPS I). A mutation in the ligand for Fas (Fas ligand; CD95 ligand, Apo-1 ligand), which induces apoptosis upon binding to Fas, was described in a patient with systemic lupus erythematodes and lymphadenopathy. Perforin, an other cytotoxic protein employed by T- and NK-cells for target cell killing, is mutated in chromosome 10 linked cases of familial hemophagocytic lymphohistiocytosis. Caspase 10, a representative of the caspase family of proteases, which plays a central role in the execution of apoptosis, is defect in autoimmune lymphoproliferative syndrome type II (ALPS II). The intracellular pro-apoptotic molecule bcl-10 is frequently mutated in mucosa-associated lymphoid tissue (MALT) lymphomas and various non-hematologic malignancies. The p53, an executioner of DNA damage triggered apoptosis, and Bax, a pro-apoptotic molecule with the ability to perturb mitochondrial membrane integrity, are frequently mutated in malignant neoplasms. Anti-apoptotic proteins like bcl-2, cellular-inhibitor of apoptosis protein 2 (c-IAP2) and neuronal apoptosis inhibitory protein 1 (NAIP1) are often altered in follicular lymphomas, MALT lymphomas and spinal muscular atrophy (SMA), respectively. This article reviews the current knowledge on mutations 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.
authors.affiliation: Institute of Clinical Pathology, University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. leonard.muellauer@akh-wien.ac.at
authors.forename: L
authors.initials: L
authors.lastname: Müllauer
authors.forename: P
authors.initials: P
authors.lastname: Gruber
authors.forename: D
authors.initials: D
authors.lastname: Sebinger
authors.forename: J
authors.initials: J
authors.lastname: Buch
authors.forename: S
authors.initials: S
authors.lastname: Wohlfart
authors.forename: A
authors.initials: A
authors.lastname: Chott
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases / Q000235:genetics / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics / Q000502:physiology; D015195:Drug Design; D053222:Fas Ligand Protein; D005544:Forecasting; D019254:Genes, bcl-2; D016158:Genes, p53; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D051616:Neuronal Apoptosis-Inhibitory Protein; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011379:Prognosis; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C494826:BAX protein, human; C118591:BCL10 protein, human; D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; C496800:NAIP protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; D052899:Pore Forming Cytotoxic Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D054353:Perforin; D020169:Caspases