Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome

doi:10.1016/j.molimm.2006.07.004

Molecular Immunology

Volume 44, Issues 1–3, January 2007, Pages 111-122

https://doi.org/10.1016/j.molimm.2006.07.004 Get rights and content

Abstract

The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D + HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.

Section snippets

Classification

The hemolytic uremic syndrome (HUS) is defined as the clinical triad of microangiopathic anemia, thrombocytopenia and acute renal failure (Richards et al., 2002). There are two types, diarrheal-associated HUS (D+ HUS) and non-diarrheal or atypical HUS (aHUS). Both forms of HUS are characterized pathologically by a thrombotic microangiopathy (TMA), defined by vessel wall thickening and intraluminal fibrin/platelet thrombi. In D+ HUS, the TMA is localized to the glomerular capillaries, whilst in

Identification and expression

Membrane cofactor protein (MCP; CD46) was initially identified as a C3b and C4b binding protein of human peripheral blood cells that co-purified in affinity chromatography with complement receptors one and two (Cole et al., 1985). It was subsequently shown to possess cofactor activity (CA) for these two complement fragments that deposit on a target (Seya et al., 1986).

It is a widely expressed transmembrane complement regulator, present on most cells (except erythrocytes, in man). It is highly

MCP mutations in aHUS (Fig. 1; Tables 2a and 2b)

The first identification of mutations in the gene for MCP with a human disease was made in 2003. The gene for MCP was screened in 30 families with aHUS using direct fluorescent sequencing (Richards et al., 2003). In one family, initially described by Pirson et al. (1987), three affected brothers had an in-frame six-base pair deletion leading to loss of D237/S238 in CCP 4. FACS analysis showed ∼50% levels of MCP expression on PBMC lysates from the patients. There was also a reduction in C3b

Understanding the role of MCP in the pathogenesis of the aHUS

Mutations in the complement regulatory proteins CFH, MCP and IF are recognized predisposing factors for the development of aHUS. These data implicate cofactor activity for C3b, provided by IF plus its cofactors MCP or CFH, as being required to protect kidney endothelial cells as well as their underlying glomerular basement membrane from the development of an undesirable thrombotic microangiopathy (Fig. 2a). A decrease in function of any one of these three proteins in the kidney glomerulus leads

Outcome of MCP-associated aHUS

aHUS has a poor outcome overall with ∼50% of patients developing end-stage renal failure and ∼25% acute phase mortality (Noris and Remuzzi, 2005). However, patients with mutations in CFH have more severe disease compared to those with mutations in MCP (Caprioli et al., in press). Seventy percent of those with CFH-HUS develop ESRF or die, whilst 86% with MCP-HUS remain dialysis-independent, despite recurrent disease. Recurrence of aHUS occurred in ∼70% of patients with MCP-HUS who did not

Conclusions

Mutations in MCP predispose to the development of aHUS by leading to insufficient regulation of complement at times of renal endothelial cell injury. Incomplete penetrance of mutations is, however, high (∼50%) and the development of aHUS is likely to require additional genetic and environmental triggers. The outcome for those with MCP mutations as a cause of aHUS is favorable. Renal transplantation has been performed in ten cases, only one of which was complicated by recurrent aHUS. The

Acknowledgments

We would like to thank Madonna Bogacki for assistance with manuscript preparation. A.R. is supported by the Fulbright US/UK exchange programme and the Peel Medical Research Trust. D.K. is supported by Kidney Research UK and the Peel Medical Research Trust. T.H.J.G. is supported by the Foundation for Children with atypical HUS and the Robin Davies Trust. M.K.L. and J.P.A. are supported by NIH RO1 AI37618. C.J.F. is supported by NIH T32 AR07279. E.M. is supported by NIH T32 HL07317.

References (76)

M. Buddles et al.
Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uraemic syndrome
Am. J. Hum. Genet.
(2000)
A.R. Constantinescu et al.
Non-enteropathic hemolytic uremic syndrome: causes and short-term course
Am. J. Kidney Dis.
(2004)
R.E. Dorig et al.
The human CD46 molecule is a receptor for measles virus (Edmonston strain)
Cell
(1993)
J. Esparza-Gordillo et al.
Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree
Mol. Immunol.
(2006)
D. Hourcade et al.
The regulators of complement activation (RCA) gene cluster
Adv. Immunol.
(1989)
B. Kaplan et al.
Renal transplantation in adults with autosomal recessive inheritance of hemolytic uremic syndrome
Am. J. Kidney Dis.
(1997)
M. Karmali et al.
Sporadic cases of haemolytic uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli in stools
Lancet
(1983)
M.K. Liszewski et al.
Membrane cofactor protein (CD46) of complement: processing differences related to alternatively spliced cytoplasmic domains
J. Biol. Chem.
(1994)
M.K. Liszewski et al.
Dissecting sites important for complement regulatory activity in membrane cofactor protein (MCP; CD46)
J. Biol. Chem.
(2000)
S. Mungall et al.
Hemolytic uremic syndrome in metastatic adenocarcinoma of the prostate
Am. J. Kidney Dis.
(2002)

M. Nangaku

Complement regulatory proteins in glomerular diseases

Kidney Int.

(1998)

M. Noris et al.

Familial haemolytic uraemic syndrome and an MCP mutation

Lancet

(2003)

D. Perez-Caballero et al.

Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome

Am. J. Hum. Genet.

(2001)

A. Richards et al.

Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition

Am. J. Hum. Genet.

(2001)

R.C. Riley-Vargas et al.

CD46: expanding beyond complement regulation

Trends Immunol.

(2004)

P. Sanchez-Corral et al.

Structural and functional characterization of factor H mutations associated with atypical haemolytic uraemic syndrome

Am. J. Hum. Genet.

(2002)

P. Sanchez-Corral et al.

Functional analysis in serum from atypical Hemolytic Uremic Syndrome patients reveals impaired protection of host cells associated with mutations in factor H

Mol. Immunol.

(2004)

F. Santoro et al.

Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46

J. Biol. Chem.

(2003)

P. Warwicker et al.

Genetic studies into inherited and sporadic hemolytic uremic syndrome

Kidney Int.

(1998)

E.M. Adams et al.

Contribution of the repeating domains of membrane cofactor protein (CD46) of the complement system to ligand binding and cofactor activity

J. Immunol.

(1991)

L. Ballard et al.

A polymorphism of the complement regulatory protein MCP (membrane cofactor protein or gp 45–70)

J. Immunol.

(1987)

M.L. Barilla-LaBarca et al.

Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells

J. Immunol.

(2002)

S. Becker et al.

HIV-associated thrombotic microangiopathy in the era of highly active antiretroviral therapy: an observational study

Clin. Infect. Dis.

(2004)

N.S. Bora et al.

Structural gene for human membrane cofactor protein (MCP) of complement maps to within 100 kb of the 3′ end of the C3b/C4b receptor gene

J. Exp. Med.

(1989)

E. Bresin et al.

Outcome of renal transplantation in patients with non-Shiga toxin-associated haemolytic uraemic synbdrome: prognostic significance of genetic background

Clin. J. Am. Soc. Nephrol.

(2006)

R.A. Brooimans et al.

Biosynthesis of complement factor H by human umbilical vein endothelial cells. Regulation by T cell growth factor and IFN-gamma

J. Immunol.

(1989)

J. Caprioli et al.

The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20

J. Am. Soc. Nephrol.

(2001)

J. Caprioli et al.

Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease

Hum. Mol. Genet.

(2003)

Caprioli, J., Noris, M., Brioschi, S., Pianetti, G., Castelletti, F., Bettinaglio, P., Mele, C., Bresin, E., Cassis,...

J.M. Casasnovas et al.

Crystal structure of two CD46 domains reveals an extended measles virus-binding surface

EMBO J.

(1999)

J.L. Cole et al.

Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines

Proc. Natl. Acad. Sci. U.S.A.

(1985)

W. Cui et al.

Characterization of the promoter region of the membrane cofactor protein (CD46) gene of the human complement system and comparison to a membrane cofactor protein-like genetic element

J. Immunol.

(1993)

P. Devaux et al.

Control of C3b and C5b deposition by CD46 (membrane cofactor protein) after alternative but not classical complement activation

Eur. J. Immunol.

(1999)

J.S. Dlott et al.

Drug-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a concise review

Ther. Apher. Dial.

(2004)

M.-A. Dragon-Durey et al.

Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases

J. Am. Soc. Nephrol.

(2004)

M.-A. Dragon-Durey et al.

Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome

J. Am. Soc. Nephrol.

(2005)

J. Esparza-Gordillo et al.

Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32

Hum. Mol. Genet.

(2005)

J. Esparza-Gordillo et al.

Corrigendum. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32

Hum. Mol. Genet.

(2005)

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Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome

Abstract

Section snippets

Classification

Identification and expression

MCP mutations in aHUS (Fig. 1; Tables 2a and 2b)

Understanding the role of MCP in the pathogenesis of the aHUS

Outcome of MCP-associated aHUS

Conclusions

Acknowledgments

Am. J. Hum. Genet.

Am. J. Kidney Dis.

Cell

Mol. Immunol.

Adv. Immunol.

Am. J. Kidney Dis.

Lancet

J. Biol. Chem.

J. Biol. Chem.

Am. J. Kidney Dis.

Kidney Int.

Lancet

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Trends Immunol.

Am. J. Hum. Genet.

Mol. Immunol.

J. Biol. Chem.

Kidney Int.

Contribution of the repeating domains of membrane cofactor protein (CD46) of the complement system to ligand binding and cofactor activity

J. Immunol.

A polymorphism of the complement regulatory protein MCP (membrane cofactor protein or gp 45–70)

J. Immunol.

Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells

J. Immunol.

HIV-associated thrombotic microangiopathy in the era of highly active antiretroviral therapy: an observational study

Clin. Infect. Dis.

Structural gene for human membrane cofactor protein (MCP) of complement maps to within 100 kb of the 3′ end of the C3b/C4b receptor gene

J. Exp. Med.

Outcome of renal transplantation in patients with non-Shiga toxin-associated haemolytic uraemic synbdrome: prognostic significance of genetic background

Clin. J. Am. Soc. Nephrol.

Biosynthesis of complement factor H by human umbilical vein endothelial cells. Regulation by T cell growth factor and IFN-gamma

J. Immunol.

The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20

J. Am. Soc. Nephrol.

Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease

Hum. Mol. Genet.

Crystal structure of two CD46 domains reveals an extended measles virus-binding surface

EMBO J.

Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines

Proc. Natl. Acad. Sci. U.S.A.

Characterization of the promoter region of the membrane cofactor protein (CD46) gene of the human complement system and comparison to a membrane cofactor protein-like genetic element

J. Immunol.

Control of C3b and C5b deposition by CD46 (membrane cofactor protein) after alternative but not classical complement activation

Eur. J. Immunol.

Drug-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a concise review

Ther. Apher. Dial.

Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases

J. Am. Soc. Nephrol.

Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome

J. Am. Soc. Nephrol.

Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32

Hum. Mol. Genet.

Corrigendum. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32

Hum. Mol. Genet.