Familial haemolytic uraemic syndrome and an MCP mutation

Noris, Marina; Brioschi, Simona; Caprioli, Jessica; Todeschini, Marta; Bresin, Elena; Porrati, Francesca; Gamba, Sara; Remuzzi, Giuseppe

doi:10.1016/s0140-6736(03)14742-3

Cited by 287 publications

(152 citation statements)

References 25 publications

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“…A characteristic feature of MCP and factor H associated HUS is a variable penetrance and inheritance. In one panel of families, disease penetrance was ~50% (Richards et al, 2001;Richards et al, 2003), and these results are consistent with several other series (Fremeaux-Bacchi et al, 2006;Noris et al, 2003). Further, these patients are healthy prior to their first episode of aHUS and many recover only to have another attack years later.…”

Section: Discussionsupporting

confidence: 88%

“…Some patients with the MCP deficiency show reduced expression levels on peripheral blood mononuclear cells (PBMC) (Esparza-Gordillo et al, 2005;Noris et al, 2003;Richards et al, 2003). Our data demonstrate that reduced MCP expression correlates with increased complement dysregulation.…”

Section: Discussionmentioning

confidence: 75%

“…The lack of appropriate complement control in aHUS leads to a procoagulant state with microthrombi formation in the renal vasculature (Atkinson et Heterozygous individuals of all three regulators are affected, suggesting that half-normal levels of these proteins are insufficient to protect kidney vessels. In the case of MCP, more than 75% of the mutations cause a reduction in expression (Caprioli et al, 2006;Esparza-Gordillo et al, 2005;Fremeaux-Bacchi et al, 2006;Noris et al, 2003;Richards et al, 2003;Richards et al, In Press). Kidney transplantation is a treatment strategy primarily effective for patients with MCP mutations since the transplanted kidney should express normal levels of MCP.…”

Section: Discussionmentioning

confidence: 99%

“…1C) (Liszewski et al, 2000;Richards et al, 2003). Currently, ~20 different MCP mutations have been identified and partially characterized in aHUS (Caprioli et al, 2006;Esparza-Gordillo et al, 2005;Fremeaux-Bacchi et al, 2006;Noris et al, 2003;Richards et al, 2003). Many result in a premature stop codon or produce a mutant protein that is retained in the endoplasmic reticulum and degraded intracellularly [reviewed (Richards et al, In Press)].…”

Section: Discussionmentioning

confidence: 99%

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Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

Liszewski

Leung

Schraml

et al. 2007

Molecular Immunology

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Mutations in complement regulatory proteins predispose to the development of aHUS. Approximately 50% of patients bear a mutation in one of three complement control proteins, factor H, factor I, or membrane cofactor protein (MCP; CD46). Another membrane regulator that is closely related to MCP, decay accelerating factor (DAF; CD55) thus far has shown no association with aHUS and continues to be investigated. The goal of this study was to compare the regulatory profile of MCP and DAF and to assess how alterations in MCP predispose to complement dysregulation. We employed a model system of complement activation on Chinese hamster ovary (CHO) cell transfectants. The four regularly expressed isoforms of MCP and DAF inhibited C3b deposition by the alternative pathway. DAF, but not MCP, inhibited the classical pathway. Most patients with MCPaHUS are heterozygous and express only 25-50 % of the wild-type protein. We, therefore, analyzed the effect of reduced levels of wild-type MCP and found that cells with lowered expression levels were less efficient in inhibiting alternative pathway activation. Further, a dysfunctional MCP mutant, expressed at normal levels and identified in five patients with aHUS (S206P), failed to protect against C3b amplification on CHO cells, even if expression levels were increased 10-fold. Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

Liszewski

Leung

Schraml

et al. 2007

Molecular Immunology

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“…Non-Shiga-toxin-associated HUS, or atypical HUS (aHUS), has been associated with mutations of the fluid phase alternative pathway inhibitor factor H (49 -51), the membrane-bound inhibitor membrane cofactor protein (CD46) (52,53), factor I (54), and autoantibodies to factor H (55). Alternative pathway activation during the disease has been detected by decreased levels of C3 and factor B as well as increased levels of C3 activation fragments (56 -58), whereas C4 levels are unaffected (56).…”

Section: Atypical Hemolytic-uremic Syndrome (Hus)mentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

The Journal of Immunology

391

350

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The complement system is increasingly recognized as important in the pathogenesis of tissue injury in vivo following immune, ischemic, or infectious insults. Within the complement system, three pathways are capable of initiating the processes that result in C3 activation: classical, alternative, and lectin. Although the roles that proinflammatory peptides and complexes generated during complement activation play in mediating disease processes have been studied extensively, the relative contributions of the three activating pathways is less well understood. Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation products in vivo. In addition, we discuss new concepts regarding the mechanisms by which the alternative pathway is activated in vivo, as recent clinical findings and experimental results have provided evidence that continuous active control of this pathway is necessary to prevent unintended targeting and injury to self tissues.

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Laboratory tests for disorders of complement and complement regulatory proteins

Shih

Murali

2015

American J Hematol

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The complement pathway is a cascade of proteases that is involved in immune surveillance and innate immunity, as well as adaptive immunity. Dysfunction of the complement cascade may be mediated by aberrations in the pathways of activation, complement regulatory proteins, or complement deficiencies, and has been linked to a number of hematologic disorders, including paroxysmal noctural hemoglobinuria (PNH), hereditary angioedema (HAE), and atypical hemolytic-uremic syndrome (aHUS). Here, current laboratory tests for disorders of the complement pathway are reviewed, and their utility and limitations in hematologic disorders and systemic diseases are discussed. Current therapeutic advances targeting the complement pathway in treatment of complement-mediated hematologic disorders are also reviewed.

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Familial haemolytic uraemic syndrome and an MCP mutation

Cited by 287 publications

References 25 publications

Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

The Central Role of the Alternative Complement Pathway in Human Disease

Laboratory tests for disorders of complement and complement regulatory proteins

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