Document Detail

Whole-exome-sequencing-based discovery of human FADD deficiency.
MedLine Citation:
PMID:  21109225     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-25
Journal Detail:
Title:  American journal of human genetics     Volume:  87     ISSN:  1537-6605     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-07     Completed Date:  2011-01-18     Revised Date:  2014-09-09    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  873-81     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Amino Acid Sequence
Autoimmune Lymphoproliferative Syndrome / genetics*
Fas-Associated Death Domain Protein / chemistry,  genetics*
Molecular Sequence Data
Mutation, Missense
Sequence Analysis, DNA*
Sequence Homology, Amino Acid
Grant Support
5UL1RR024143-03/RR/NCRR NIH HHS; G0701897//Medical Research Council; R01 AA017238/AA/NIAAA NIH HHS; R01AA017238/AA/NIAAA NIH HHS
Reg. No./Substance:
0/FADD protein, human; 0/Fas-Associated Death Domain Protein

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