Title |
Whole-Exome-Sequencing-Based Discovery of Human FADD Deficiency
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Published in |
American Journal of Human Genetics, November 2010
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DOI | 10.1016/j.ajhg.2010.10.028 |
Pubmed ID | |
Authors |
Alexandre Bolze, Minji Byun, David McDonald, Neil V. Morgan, Avinash Abhyankar, Lakshmanane Premkumar, Anne Puel, Chris M. Bacon, Frédéric Rieux-Laucat, Ki Pang, Alison Britland, Laurent Abel, Andrew Cant, Eamonn R. Maher, Stefan J. Riedl, Sophie Hambleton, Jean-Laurent Casanova |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 50% |
United Kingdom | 1 | 50% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 1 | 50% |
Members of the public | 1 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | 1% |
United States | 2 | 1% |
Spain | 2 | 1% |
Norway | 1 | <1% |
Canada | 1 | <1% |
India | 1 | <1% |
Germany | 1 | <1% |
China | 1 | <1% |
Unknown | 155 | 93% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 39 | 23% |
Researcher | 28 | 17% |
Student > Postgraduate | 15 | 9% |
Student > Master | 15 | 9% |
Professor | 11 | 7% |
Other | 36 | 22% |
Unknown | 22 | 13% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 54 | 33% |
Medicine and Dentistry | 35 | 21% |
Biochemistry, Genetics and Molecular Biology | 30 | 18% |
Immunology and Microbiology | 10 | 6% |
Computer Science | 4 | 2% |
Other | 10 | 6% |
Unknown | 23 | 14% |