Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome

*Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain;
^†Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, United Kingdom;
^‡Servicio de Nefrología, Hospital Universitario de Bellvitge, Feixa Llarga s/n 08907 Barcelona, Spain; and
^§Unidades de Investigación y
^¶Inmunología, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain

Edited by Douglas T. Fearon, University of Cambridge, Cambridge, United Kingdom, and approved October 25, 2006 (received for review May 2, 2006)

Abstract

Hemolytic uremic syndrome (HUS) is an important cause of acute renal failure in children. Mutations in one or more genes encoding complement-regulatory proteins have been reported in approximately one-third of nondiarrheal, atypical HUS (aHUS) patients, suggesting a defect in the protection of cell surfaces against complement activation in susceptible individuals. Here, we identified a subgroup of aHUS patients showing persistent activation of the complement alternative pathway and found within this subgroup two families with mutations in the gene encoding factor B (BF), a zymogen that carries the catalytic site of the complement alternative pathway convertase (C3bBb). Functional analyses demonstrated that F286L and K323E aHUS-associated BF mutations are gain-of-function mutations that result in enhanced formation of the C3bBb convertase or increased resistance to inactivation by complement regulators. These data expand our understanding of the genetic factors conferring predisposition to aHUS, demonstrate the critical role of the alternative complement pathway in the pathogenesis of aHUS, and provide support for the use of complement-inhibition therapies to prevent or reduce tissue damage caused by dysregulated complement activation.

renal disease

Footnotes

^‖To whom correspondence should be addressed. E-mail: srdecordoba{at}cib.csic.es
Author contributions: E.G.d.J. and C.L.H. contributed equally to this work; E.G.d.J., C.L.H., J.E.-G., B.P.M., and S.R.d.C. designed research; E.G.d.J., C.L.H., J.E.-G., E.A.A., C.A.G., P.S.-C., B.P.M., and S.R.d.C. performed research; P.S.-C. contributed new reagents/analytic tools; E.G.d.J., C.L.H., J.E.-G., L.C., M.L.-T., P.S.-C., B.P.M., and S.R.d.C. analyzed data; and E.G.d.J., C.L.H., B.P.M., and S.R.d.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0603420103/DC1.
Abbreviations:

aHUS,

atypical HUS;

HUS,

hemolytic uremic syndrome;

SPR,

surface plasmon resonance;

vWfA,

von Willebrand factor type A.