Skip to main content
eScholarship
Open Access Publications from the University of California

UCSF

UC San Francisco Previously Published Works bannerUCSF

Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib.

  • Author(s): Bi, Lilia L
  • Pan, George
  • Atkinson, T Prescott
  • Zheng, Lixin
  • Dale, Janet K
  • Makris, Christopher
  • Reddy, Vishnu
  • McDonald, Jay M
  • Siegel, Richard M
  • Puck, Jennifer M
  • Lenardo, Michael J
  • Straus, Stephen E
  • et al.
Abstract

Background

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance due primarily to genetic defects in Fas (CD95/APO-1; TNFRSF6), a cell surface receptor that regulates apoptosis and its signaling apparatus.

Methods

Fas ligand gene mutations from ALPS patients were identified through cDNA and genomic DNA sequencing. Molecular and biochemical assessment of these mutant Fas ligand proteins were carried out by expressing the mutant FasL cDNA in mammalian cells and analysis its effects on Fas-mediated programmed cell death.

Results

We found an ALPS patient that harbored a heterozygous A530G mutation in the FasL gene that replaced Arg with Gly at position 156 in the protein's extracellular Fas-binding region. This produced a dominant-interfering FasL protein that bound to the wild-type FasL protein and prevented it from effectively inducing apoptosis.

Conclusion

Our data explain how a naturally occurring heterozygous human FasL mutation can dominantly interfere with normal FasL apoptotic function and lead to an ALPS phenotype, designated Type Ib.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
Current View