Whole-exome-sequencing-based discovery of human FADD deficiency.
Germline mutations in FASL and FAS impair Fas-dependent apoptosis and cause recessively or dominantly inherited autoimmune lymphoproliferative syndrome (ALPS). Patients with ALPS typically present with no other clinical phenotype. We investigated a large, consanguineous, multiplex kindred in which biological features of ALPS were found in the context of severe bacterial and viral disease, recurrent hepatopathy and encephalopathy, and cardiac malformations. By a combination of genome-wide linkage and whole-exome sequencing, we identified a homozygous missense mutation in FADD, encoding the Fas-associated death domain protein (FADD), in the patients. This FADD mutation decreases steady-state protein levels and impairs Fas-dependent apoptosis in vitro, accounting for biological ALPS phenotypes in vivo. It also impairs Fas-independent signaling pathways. The observed bacterial infections result partly from functional hyposplenism, and viral infections result from impaired interferon immunity. We describe here a complex clinical disorder, its genetic basis, and some of the key mechanisms underlying its pathogenesis. Our findings highlight the key role of FADD in Fas-dependent and Fas-independent signaling pathways in humans.
The Rockefeller University, New York, NY 10065, USA.
Alexandre
A
Bolze
Minji
M
Byun
David
D
McDonald
Neil V
NV
Morgan
Avinash
A
Abhyankar
Lakshmanane
L
Premkumar
Anne
A
Puel
Chris M
CM
Bacon
Frédéric
F
Rieux-Laucat
Ki
K
Pang
Alison
A
Britland
Laurent
L
Abel
Andrew
A
Cant
Eamonn R
ER
Maher
Stefan J
SJ
Riedl
Sophie
S
Hambleton
Jean-Laurent
JL
Casanova
D000595:Amino Acid Sequence; D000818:Animals; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics*; D005091:Exons; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein