Dominant Interfering Fas Gene Mutations Impair Apoptosis in a Human Autoimmune Lymphoproliferative Syndrome

Cell. 1995 Jun 16;81(6):935-46. doi: 10.1016/0092-8674(95)90013-6.

Abstract

Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+CD4-CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child had defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of lymphocyte homeostasis and peripheral self-tolerance.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens, Surface / genetics*
  • Apoptosis / genetics*
  • Apoptosis / immunology*
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • Base Sequence
  • Child, Preschool
  • DNA Primers / genetics
  • DNA, Complementary / genetics
  • Female
  • Genes, Dominant
  • Heterozygote
  • Humans
  • Infant
  • Lymphoproliferative Disorders / genetics*
  • Lymphoproliferative Disorders / immunology*
  • Lymphoproliferative Disorders / pathology
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Phenotype
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocyte Subsets / immunology
  • fas Receptor

Substances

  • Antigens, Surface
  • DNA Primers
  • DNA, Complementary
  • Receptors, Antigen, T-Cell
  • fas Receptor