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Open Access Highly Accessed Research article

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

Lilia L Bi1, George Pan6, T Prescott Atkinson7, Lixin Zheng3*, Janet K Dale2, Christopher Makris7, Vishnu Reddy6, Jay M McDonald68, Richard M Siegel5, Jennifer M Puck4, Michael J Lenardo3* and Stephen E Straus2

Author Affiliations

1 Center for Biologics Evaluation and Research, FDA, Rockville, Maryland, USA

2 Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA

3 Laboratory of Immunology, NIAID, NIH, Bethesda, MD 20892, USA

4 Department of Pediatrics, University of California, San Francisco, USA

5 Autoimmunity Branch, NIAMS, NIH, Bethesda, MD 20892, USA

6 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA

7 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA

8 The Birmingham Veteran's Administration Medical Center, Birmingham, Alabama, USA

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BMC Medical Genetics 2007, 8:41  doi:10.1186/1471-2350-8-41

Published: 2 July 2007

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.