Genetics and complement in atypical HUS - PubMed (original) (raw)

Review

Genetics and complement in atypical HUS

David Kavanagh et al. Pediatr Nephrol. 2010 Dec.

Abstract

Central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS) is over-activation of the alternative pathway of complement. Following the initial discovery of mutations in the complement regulatory protein, factor H, mutations have been described in factor I, membrane cofactor protein and thrombomodulin, which also result in decreased complement regulation. Autoantibodies to factor H have also been reported to impair complement regulation in aHUS. More recently, gain of function mutations in the complement components C3 and Factor B have been seen. This review focuses on the genetic causes of aHUS, their functional consequences, and clinical effect.

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Figures

Fig. 1

Fig. 1

Complement regulation. The alternative complement pathway (AP) is a positive-feedback amplification loop. The AP constantly undergoes tick over but can also be primed by the classical (CP) and lectin (LP) pathways. The C3b that is formed interacts with factor B (B), which is then cleaved by factor D (D) to form the AP C3 convertase (C3bBb). This enzyme complex is attached to the target covalently via C3b while Bb is the catalytic serine protease subunit. It is stabilized by binding properdin (P). Because C3 is the substrate for this convertase, a powerful feedback loop is created. Unchecked, this will lead to activation of the terminal complement pathway with generation of the effector molecules; the anaphylatoxin C5a and the membrane attack complex (MAC). To limit damage to host cells, the AP is down-regulated by cofactor activity (CA) and decay accelerating activity (DAA). CA results in the permanent inactivation of C3b to iC3b, such that it is no longer capable of binding B and thus cannot form the AP convertase. CA requires both a cofactor protein (factor H [fH] or membrane cofactor protein [MCP]) and a protease, factor I (fI). DAA is the dissociation of the C3/C5 convertases. The decay accelerator protein, in this example decay accelerating factor (DAF), displaces the catalytic Bb from target-bound C3b. However, this C3b can bind another B and then reform the convertase

Fig. 2

Fig. 2

Complement factor H and complement factor H-related 1. The figure demonstrates the 20 CCP modules of factor H (bottom) and the five CCP modules of factor H-related protein 1 (top). The homology of each factor H-related protein 1 CCP to the corresponding factor H CCP is given as a percentage in the factor H-related protein 1 figure. Note the homology between CCP18 of factor H and CCP 3 of factor H-related protein 1 is given for the basic isoform. An acidic isoform differs by three amino acids [62]. The glycosaminoglycan and C3b binding sites of factor H are indicated on the diagram. Mutations in CFH reported in aHUS are listed below the figure

Fig. 3

Fig. 3

Membrane cofactor protein. The figure demonstrates clustering of mutations in the four extracellular CCP domains of membrane cofactor protein in aHUS. * denotes mutations resulting in decreased cell surface expression of membrane cofactor protein

Fig. 4

Fig. 4

Complement factor I. The figure demonstrates the modular structure of factor I with aHUS-associated mutations below. $ denotes factor I mutants that are secreted but have been demonstrated to have decreased activity. * denotes factor I mutants that have impaired secretion

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References

    1. Kavanagh D, Richards A, Atkinson J. Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med. 2008;59:293–309. doi: 10.1146/annurev.med.59.060106.185110. - DOI - PubMed
    1. Fogo A, Kashgarian M. Diagnostic atlas of renal pathology. Amsterdam: Elsevier Science; 2005.
    1. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365:1073–1086. - PubMed
    1. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16:1035–1050. doi: 10.1681/ASN.2004100861. - DOI - PubMed
    1. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Kar N, Vandewalle J, Zimmerhackl LB. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24:687–696. doi: 10.1007/s00467-008-0964-1. - DOI - PubMed

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