MUTATIONS OF PROGRAMMED CELL DEATH GENE FAS

Human Genome Research

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Abstract

Subjects and their family members have been studied who have a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive non-malignant lymphadenopathy, defective lymphocyte programmed cell death, or apoptosis, expanded populations of CD4-, CD8- lymphocytes, and autoimmune diseases such as anemia and low platelets (bleeding disorders). Most patients have unique, deleterious mutations in the Fas gene. The heterozygous mutations produce defective proteins which interfere with apoptosis when they are co-expressed with normal Fas. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients indicates an involvement of Fas in this newly recognized disorder. Family studies demonstrate that the inheritance of the mutant Fas alleles causes a dominantly inherited cellular apoptosis defect. However, overt autoimmunity requires additional factors besides heterozygous Fas mutation. In families in which several people had a dominant negative Fas mutation, clinical abnormalities ranged from benign lymphadenopathy to autoimmune disease with elevated double negative T cells to Hodgkinis disease and non-Hodgkins lymphoma. Fas and other proteins which participate in lymphocyte apoptosis might function as oncogenes in the development of cancer. In addition a transgenic mouse model of dominant negative Fas mutations was developed. Genetic factors that influence how severe a patients symptoms will be are being sought. - Immunology, Pediatric Research, Gene Mapping, Genetics, Hematology, Lupus - Human Subjects & Human Subjects: Interview, Questionaires, or Surveys Only