This increased germ cell death is blocked by a gain-of-function mutation of the Bcl-2 homolog CED-9 and requires functional caspase CED-3 and the APAF-1 homolog CED-4. Disrupting the function of the cisd genes resulted in various germline abnormalities including distal tip cell migration defects and a significant increase in the number of cell corpses within the adult germline. elegans genome contains three previously uncharacterized cisd genes that code for CISD-1, which has homology to mitoNEET/CISD1 and NAF-1/CISD2, and CISD-3.1 and CISD-3.2, both of which have homology to Miner2/CISD3. In humans, mutations in CISD2 result in Wolfram syndrome 2, a disease in which the patients display juvenile diabetes, neuropsychiatric disorders and defective platelet aggregation. Other members of the CDGSH iron sulfur domain (CISD) family include mitoNEET/CISD1 and Miner2/CISD3. The human iron–sulfur binding protein NAF-1/CISD2 binds to Bcl-2 and its disruption in cells leads to an increase in apoptosis. Programmed cell death, which occurs through a conserved core molecular pathway, is important for fundamental developmental and homeostatic processes.
