Implications physiopathologiques des altérations des gènes impliqués dans la régulation de la mort cellulaire

Cell death by apoptosis is a fundamental process that regulates tissue development and homeostasis. Deregulation of this process is involved in a number of human diseases and this deregulation can be related to inherited or acquired genetic abnormalities of proteins involved in the death machinery. Most inherited mutations interfere with the death receptor signalling pathways, including Fas, Fas-ligand or caspase-10 mutations in the Canale-Smith syndrome, deletion of NEMO (IKKγ) gene in familial incontinentia pigmenti and mutations in the extracellular domains of the 55 kDa TNF receptor in a dominant autoinflammatory syndrome. Familial Mediterranean fever was related to mutations in the MEFV gene whose product interacts with the pro-apoptotic protein ASC. Perforin gene defects were identified in familial hemophagocytic lymphohistiocytosis whereas alterations of naip gene, that encodes a caspase inhibitory protein, increase the severity of spinal amyotrophy. In human tumors, three mechanisms were observed to account for acquired cell death gene alteration: chromosomal translocation leading to overexpression of a normal (Bcl-2) or mutated (Bcl-10, c-IAP2) protein, gene mutation leading to functional alterations of the protein (p53, Fas, Box) and gene promoter hypermethylation that prevents the protein expression (caspase 8, Apaf-1, DAP kinase, TMS1). Depending on the disease, these genetic abnormalities can now be used as diagnostic tools, prognostic markers and therapeutic targets.