Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II

Cell. 1999 Jul 9;98(1):47-58. doi: 10.1016/S0092-8674(00)80605-4.

Abstract

Caspases are cysteine proteases that mediate programmed cell death in phylogenetically diverse multicellular organisms. We report here two kindreds with autoimmune lymphoproliferative syndrome (ALPS) type II, characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects, that harbor independent missense mutations in Caspase 10. These encode amino acid substitutions that decrease caspase activity and interfere with death receptor-induced apoptosis, particularly that stimulated by Fas ligand and TRAIL. These results provide evidence that inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Substitution
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology
  • Breast Neoplasms
  • Carrier Proteins / physiology
  • Caspase 10
  • Caspases / genetics*
  • Cells, Cultured
  • Child
  • DNA Primers
  • Dendritic Cells / pathology
  • Dendritic Cells / physiology*
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Female
  • HeLa Cells
  • Homeostasis
  • Humans
  • Lymphocytes / pathology
  • Lymphocytes / physiology*
  • Lymphoproliferative Disorders / enzymology
  • Lymphoproliferative Disorders / genetics*
  • Lymphoproliferative Disorders / immunology
  • Membrane Glycoproteins / physiology
  • Mutation, Missense*
  • Recombinant Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Tumor Necrosis Factor-alpha / physiology
  • fas Receptor / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DNA Primers
  • FADD protein, human
  • FASLG protein, human
  • Fas Ligand Protein
  • Fas-Associated Death Domain Protein
  • Membrane Glycoproteins
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Caspase 10
  • Caspases
  • CASP10 protein, human