| Whole-exome-sequencing-based discovery of human FADD deficiency. | |
| | |
MedLine Citation:
|
PMID: 21109225 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
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 |
Related Documents
:
|
21499015 - Jak2v617f mutation is common in old patients with polycythemia vera and essential throm... 8613205 - Angiotensin i-converting enzyme gene polymorphism and salt sensitivity in essential hyp... 21310915 - Screening of spata7 in patients with leber congenital amaurosis and severe childhood-on... 11354635 - Elite swimmers and the d allele of the ace i/d polymorphism. 7510365 - Molecular analysis of the xp-d gene in italian families with patients affected by trich... 7228875 - Caprine oligosaccharide storage disease. accumulation of beta-mannosyl (1 goes to 4) be... |
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: 2011-07-29 |
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. |
Affiliation:
|
The Rockefeller University, New York, NY 10065, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Amino Acid Sequence Animals Autoimmune Lymphoproliferative Syndrome / genetics* Exons* Fas-Associated Death Domain Protein / chemistry, genetics* Female Humans Male Molecular Sequence Data Mutation, Missense Pedigree Sequence Analysis, DNA* Sequence Homology, Amino Acid |
| Grant Support | |
ID/Acronym/Agency:
|
5UL1RR024143-03/RR/NCRR NIH HHS; G0701897//Medical Research Council; R01 AA017238-04/AA/NIAAA NIH HHS; R01AA017238/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/FADD protein, human; 0/Fas-Associated Death Domain Protein |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain...
Next Document: Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual ...