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Mutations in apoptosis genes: a pathogenetic factor for human disease
L Müllauer1, P Gruber, D Sebinger
1Institute of Clinical Pathology, University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. leonard.muellauer@akh-wien.ac.at
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.
Insights
Mutations in apoptosis genes are linked to various human diseases, including cancers and autoimmune disorders. Research into these gene mutations is crucial for developing new clinical treatments for these conditions.
Area of Science:
- Molecular Biology
- Genetics
- Immunology
Background:
- Apoptosis, or programmed cell death, is regulated by numerous gene products.
- Dysregulation of apoptosis pathways is implicated in various human diseases.
- Specific gene mutations affecting apoptosis contribute to pathologies like cancer and autoimmune syndromes.
Purpose of the Study:
- To review current knowledge on mutations in apoptosis-related genes.
- To highlight the role of these mutations in human disease pathogenesis.
- To summarize the translation of apoptosis research into clinical benefits.
Main Methods:
- Literature review of studies on apoptosis gene mutations and human diseases.
- Analysis of specific gene defects and their associated clinical conditions.
- Synthesis of findings regarding the clinical management of diseases linked to apoptosis.
Main Results:
- Defects in TNF-R1 are linked to familial periodic fever syndromes.
- Fas receptor mutations are associated with lymphomas and ALPS I.
- Mutations in Fas ligand, perforin, caspase 10, bcl-10, p53, Bax, bcl-2, c-IAP2, and NAIP1 are implicated in various cancers, autoimmune diseases, and neurological disorders.
Conclusions:
- Mutations in apoptosis genes are significant contributors to human disease.
- Understanding these mutations is vital for disease diagnosis and treatment.
- Apoptosis research offers promising avenues for clinical applications.