The anguish of India.

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. Background ALPS is a heritable disorder of lymphocyte homeostasis due to defects in apoptosis typically involving mutations in genes mediating the Fas/CD95/APO-1 pathway of programmed cell death. Patients with ALPS have chronic, nonmalignant lymphadenopathy and splenomegaly of Published: 2 July 2007 BMC Medical Genetics 2007, 8:41 doi:10.1186/1471-2350-8-41 Received: 1 December 2006 Accepted: 2 July 2007 This article is available from: http://www.biomedcentral.com/1471-2350/8/41 © 2007 Bi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.