Document Detail

Thrombomodulin mutations in atypical hemolytic-uremic syndrome.
MedLine Citation:
PMID:  19625716     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome.
METHODS: We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells.
RESULTS: Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement.
CONCLUSIONS: Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome.
Mieke Delvaeye; Marina Noris; Astrid De Vriese; Charles T Esmon; Naomi L Esmon; Gary Ferrell; Jurgen Del-Favero; Stephane Plaisance; Bart Claes; Diether Lambrechts; Carla Zoja; Giuseppe Remuzzi; Edward M Conway
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The New England journal of medicine     Volume:  361     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-23     Completed Date:  2009-07-29     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  345-57     Citation Subset:  AIM; IM    
Copyright Information:
2009 Massachusetts Medical Society
VIB-K.U.Leuven Vesalius Research Center, Leuven, Belgium.
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MeSH Terms
Complement Activation / genetics*
Complement C3b
Complement Factor I
Complement Pathway, Alternative / physiology
DNA Mutational Analysis
Hemolytic-Uremic Syndrome / genetics*,  immunology
Middle Aged
Mutation, Missense*
Polymorphism, Single Nucleotide
Thrombomodulin / genetics*,  metabolism
Young Adult
Grant Support
DK71221/DK/NIDDK NIH HHS; R21 DK071221/DK/NIDDK NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Thrombomodulin; 80295-43-8/Complement C3b; EC Factor I
Comment In:
N Engl J Med. 2009 Oct 8;361(15):1511; author reply 1511   [PMID:  19812413 ]

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