Am J Hum Genet. 2010 Dec 10;87(6):873-81. Epub 2010 Nov 25.

Whole-exome-sequencing-based discovery of human FADD deficiency.External

Bolze, A., Byun, M., McDonald, D., Morgan, N. V., Abhyankar, A., Premkumar, L., Puel, A., Bacon, C. M., Rieux-Laucat, F., Pang, K., Britland, A., Abel, L., Cant, A., Maher, E. R., Riedl, S. J., Hambleton, S., Casanova, J. L.,
--- - The Rockefeller University, New York, NY 10065, USA.
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.
PMID: 21109225External