Genomic structure and mapping of human FADD, an intracellular mediator of lymphocyte apoptosis.

Abstract

Fas-associated death domain protein (FADD)/MORT1 is a 23-kDa cytoplasmic protein containing a C-terminal death domain that interacts with the intracellular death domain of the Fas transmembrane receptor. Cross-linking of Fas mediates apoptosis in a variety of cells, primarily peripheral T lymphocytes, for which this pathway plays a major role in mature lymphocyte homeostasis. We report the characterization of the human FADD gene, which spans approximately 3.6 kb and contains two exons (286 and 341 bp) separated by a 2.0-kb intron. FADD was mapped to chromosome 11q13.3 by the independent techniques of PCR screening of somatic cell hybrid mapping panels and fluorescence in situ hybridization. In addition FADD was shown by fluorescence in situ hybridization to be amplified along with other 11q13.3 genes previously studied in the breast cancer cell line MDA-MB-134-VI, raising the possibility that overexpression of mutant FADD could contribute to poor prognosis and increased invasiveness of tumors. Its known role in apoptosis has made FADD a candidate susceptibility gene for autoimmune lymphoproliferative syndrome. Now that it has been colocalized in 11q13.3 with IDDM4, a diabetes susceptibility locus, alterations in FADD should also be considered as potential contributors to insulin-dependent familial diabetes. Elucidation of the map position and gene structure of FADD will make possible linkage and mutation analysis to study the role of this gene in human diseases.