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


CONCLUSIONS
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.
Bi
Lilia L
LL
Center for Biologics Evaluation and Research, FDA, Rockville, Maryland, USA. bi@cber.fda.gov
Pan
George
G
Atkinson
T Prescott
TP
Zheng
Lixin
L
Dale
Janet K
JK
Makris
Christopher
C
Reddy
Vishnu
V
McDonald
Jay M
JM
Siegel
Richard M
RM
Puck
Jennifer M
JM
Lenardo
Michael J
MJ
Straus
Stephen E
SE
D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000235:genetics* / Q000276:immunology; D005260:Female; D006579:Heterozygote; D006801:Humans; D019169:Jurkat Cells; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014162:Transfection
D053222:Fas Ligand Protein