TY - JOUR
T1 - Whole-Exome-Sequencing-Based Discovery of Human FADD Deficiency
AU - Bolze, A
AU - Byun, M
AU - McDonald, D
AU - Morgan, Neil
AU - Abhyankar, A
AU - Premkumar, L
AU - Puel, A
AU - Bacon, CM
AU - Rieux-Laucat, F
AU - Pang, K
AU - Britland, A
AU - Abel, L
AU - Cant, A
AU - Maher, Eamonn
AU - Riedl, SJ
AU - Hambleton, S
AU - Casanova, JL
PY - 2010/12/1
Y1 - 2010/12/1
N2 - Germline mutations in FAR. 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.
AB - Germline mutations in FAR. 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.
U2 - 10.1016/j.ajhg.2010.10.028
DO - 10.1016/j.ajhg.2010.10.028
M3 - Article
C2 - 21109225
VL - 87
SP - 873
EP - 881
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -