Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS)

Westra, Dineke; Volokhina, Elena; Heijden, Eefje van der; Vos, Annemieke; Huigen, Marleen C. D. G.; Jansen, Jitske; Kaauwen, Edwin van; Velden, Thea van der; Kar, Nicole C. A. J. van de; Heuvel, Lambert van den

doi:10.1093/ndt/gfq010

Cited by 80 publications

(64 citation statements)

References 44 publications

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“…However, the nonsubstratelike, broad-spectrum protease inhibitor diisopropyl fluorophosphate is able to react with the active site serine only if fI is preincubated with C3b (19). This requirement strongly suggests that substrate-induced remodeling of the active site is key to fI To gain insight into previously unexplained disease-associated gene polymorphisms and mutations known to alter cofactorassisted C3b/C4b cleavage by fI (21,22,32,33), we mapped them to our crystal structure (Fig. 4 and SI Appendix, Table S2).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for complement factor I control and its disease-associated sequence polymorphisms

Roversi

Johnson

Caesar

et al. 2011

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

124

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The complement system is a key component of innate and adaptive immune responses. Complement regulation is critical for prevention and control of disease. We have determined the crystal structure of the complement regulatory enzyme human factor I (fI). FI is in a proteolytically inactive form, demonstrating that it circulates in a zymogen-like state despite being fully processed to the mature sequence. Mapping of functional data from mutants of fI onto the structure suggests that this inactive form is maintained by the noncatalytic heavy-chain allosterically modulating activity of the light chain. Once the ternary complex of fI, a cofactor and a substrate is formed, the allosteric inhibition is released, and fI is oriented for cleavage. In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors. T he complement system is a major component of innate and adaptive immunity whose efficient regulation is critical for prevention and control of disease (1). This regulation is effected by host cells expressing and recruiting a series of proteins that protect them from complement-mediated destruction. A key step in this self-protection is the proteolytic cleavage of complement C3b (and its homolog C4b) by the serine protease complement factor I (fI) (2) in the presence of additional regulatory proteins termed "cofactors" (3). In the absence of regulation by fI the alternative pathway of complement leads to continuous generation of fluid-phase and cell-surface-deposited C3b by a self-amplification loop: The more C3 is converted to C3b, the more C3 convertases are formed, resulting in the depletion of C3 (4). With healthy levels of functional fI and its cofactors, the irreversible breakdown of C3b to iC3b has three effects: (i) arrest of the assembly of the C3 convertases on hostcell surfaces, thus avoiding inappropriate complement amplification; (ii) prevention of runaway C3 consumption in the fluid phase; and (iii) generation of the C3b cleavage fragments that go on to bind specific complement receptors and are involved in opsonization and triggering of the adaptive immune response (5). The importance of this regulatory mechanism is highlighted by the fact that fI-deficient individuals suffer from recurring infections and that polymorphisms in or near the genes for fI (and its cofactors) can predispose the carriers to diseases such as systemic lupus erythematosus, atypical hemolytic-uremic syndrome (aHUS), membranoproliferative glomerulonephritis, and age-related macular degeneration (for a recent review, see ref. 6).During the last few years, biochemical and structural data for complement regulators and C3/C3b in complex with regulators and inhibitors (7-11) have significantly advanced our understanding of the molecular mechanisms underlying complement regulation (12). To date, however, only low-resolution information about fI has been available (13, 14). FI is synthesized as a single 66-kDa chain an...

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Section: Resultsmentioning

confidence: 99%

Structural basis for complement factor I control and its disease-associated sequence polymorphisms

Roversi

Johnson

Caesar

et al. 2011

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

124

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“…In practice, some publications on (D-) HUS/aHUS in children include S pneumoniae -HUS, a frequent category in children [19]. Also, some publications on complement-HUS include some secondary aHUS [18,20], while others exclude the various causes indicated above (except pregnancy and contraceptive pill) [17,[21][22][23]. This may explain differences in results.…”

Section: Disease Name and Synonymsmentioning

confidence: 99%

“…In reality, the incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported from five European registries or series [17,18,[20][21][22][26][27][28] and one from the USA [23].…”

Section: Epidemiologymentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation. Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. The incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported. Onset is from the neonatal period to the adult age. Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20% have extra renal manifestations. Two to 10% die and one third progress to end-stage renal failure at first episode. Half of patients have relapses. Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. In addition, 6-10% of patients have anti-factor H antibodies. Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity > 10%). Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors). The disease is familial in approximately 20% of pedigrees, with an autosomal recessive or dominant mode of transmission. As penetrance of the disease is 50%, genetic counseling is difficult. Plasmatherapy has been first line treatment until presently, without unquestionable demonstration of efficiency. There is a high risk of post-transplant recurrence, except in MCP-HUS. Case reports and two phase II trials show an impressive efficacy of the complement C5 blocker eculizumab, suggesting it will be the next standard of care. Except for patients treated by intensive plasmatherapy or eculizumab, the worst prognosis is in factor H-HUS, as mortality can reach 20% and 50% of survivors do not recover renal function. Half of factor I-HUS progress to end-stage renal failure. Conversely, most patients with MCP-HUS have preserved renal function. Anti-factor H antibodies-HUS has favourable outcome if treated early.

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“…Thus, the genetic aberrations are important but are not sufficient for the development of aHUS. Affected patients may carry multiple mutations, in more than one gene [67,83] or a mutation in combination with the associated CFH or MCP haplotype. Family members who only carry one mutation or no polymorphisms are not affected, but this could be due to incomplete penetrance.…”

Section: Incomplete Penetrance Of Ahusmentioning

confidence: 99%

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Salvadori

Bertoni²

2013

WJN

116

111

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Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidneyliver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases Ⅰ and Ⅱ. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

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Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS)

Cited by 80 publications

References 44 publications

Structural basis for complement factor I control and its disease-associated sequence polymorphisms

Structural basis for complement factor I control and its disease-associated sequence polymorphisms

Atypical Hemolytic Uremic Syndrome

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

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