Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome

Tamara Manuelian, Jens Hellwage, Seppo Meri, Jessica Caprioli, Marina Noris, Stefan Heinen, Mihaly Jozsi, Hartmut P H Neumann, Giuseppe Remuzzi, Peter F. Zipfel

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Abstract

Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent studies have identified a factor H-associated form of HUS, caused by gene mutations that cluster in the C-terminal region of the complement regulator factor H. Here we report how three mutations (E1172Stop, R1210C, and R1215G; each of the latter two identified in three independent cases from different, unrelated families) affect protein function. All three mutations cause reduced binding to the central complement component C3b/C3d to heparin, as well as to endothelial cells. These defective features of the mutant factor H proteins explain progression of endothelial cell and microvascular damage in factor H-associated genetic HUS and indicate a protective role of factor H for tissue integrity during thrombus formation.

Original languageEnglish
Pages (from-to)1181-1190
Number of pages10
JournalJournal of Clinical Investigation
Volume111
Issue number8
DOIs
Publication statusPublished - Apr 2003

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Complement Factor H
Hemolytic-Uremic Syndrome
Heparin
Endothelial Cells
Mutation
Complement C3b
Hemolytic Anemia
Multigene Family
Acute Kidney Injury
Thrombocytopenia
Proteins
Thrombosis

ASJC Scopus subject areas

  • Medicine(all)

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Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. / Manuelian, Tamara; Hellwage, Jens; Meri, Seppo; Caprioli, Jessica; Noris, Marina; Heinen, Stefan; Jozsi, Mihaly; Neumann, Hartmut P H; Remuzzi, Giuseppe; Zipfel, Peter F.

In: Journal of Clinical Investigation, Vol. 111, No. 8, 04.2003, p. 1181-1190.

Research output: Contribution to journalArticle

Manuelian, Tamara ; Hellwage, Jens ; Meri, Seppo ; Caprioli, Jessica ; Noris, Marina ; Heinen, Stefan ; Jozsi, Mihaly ; Neumann, Hartmut P H ; Remuzzi, Giuseppe ; Zipfel, Peter F. / Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 8. pp. 1181-1190.
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AU - Manuelian, Tamara

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AU - Meri, Seppo

AU - Caprioli, Jessica

AU - Noris, Marina

AU - Heinen, Stefan

AU - Jozsi, Mihaly

AU - Neumann, Hartmut P H

AU - Remuzzi, Giuseppe

AU - Zipfel, Peter F.

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AB - Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent studies have identified a factor H-associated form of HUS, caused by gene mutations that cluster in the C-terminal region of the complement regulator factor H. Here we report how three mutations (E1172Stop, R1210C, and R1215G; each of the latter two identified in three independent cases from different, unrelated families) affect protein function. All three mutations cause reduced binding to the central complement component C3b/C3d to heparin, as well as to endothelial cells. These defective features of the mutant factor H proteins explain progression of endothelial cell and microvascular damage in factor H-associated genetic HUS and indicate a protective role of factor H for tissue integrity during thrombus formation.

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