Genetic analysis and functional characterization of novel mutations in a series of patients with atypical hemolytic uremic syndrome

Szarvas, Nóra; Szilágyi, Ágnes; Csuka, Dorottya; Takács, Beáta; Rusai, Krisztina; Müller, Thomas; Arbeiter, Klaus; Réti, Marienn; Haris, Ágnes; Wagner, László; Török, Szilárd; Kelen, Kata; Szabó, Attila; Reusz, György; Morgan, B. Paul; Prohászka, Zoltán

doi:10.1016/j.molimm.2016.01.003

Cited by 30 publications

(28 citation statements)

References 67 publications

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“…Although the molecular consequences of this polymorphism are still being explored, the C3F variant appears to be associated with an unfavorable outcome in several diseases, including IgA nephropathy, partial lipodystrophy, and systemic vasculitis . Meanwhile, numerous distinct C3 variants have been correlated with certain pathologic conditions, particularly with age‐related macular degeneration (AMD), aHUS, and C3G . Complement dysregulation is a common feature in these diseases, producing a situation featuring chronic inflammation and tissue damage .…”

Section: Too Much Too Little: Disturbed C3 Balance and Its Clinical mentioning

confidence: 99%

“…164 Meanwhile, numerous distinct C3 variants have been correlated with certain pathologic conditions, particularly with age-related macular degeneration (AMD), aHUS, and C3G. [165][166][167][168][169][170][171][172][173] Complement dysregulation is a common feature in these diseases, producing a situation featuring chronic inflammation and tissue damage. 4 Notably, the exact involvement of complement can differ between diseases and even between patients.…”

Section: Too Much Too Little: Disturbed C3 Balance and Its Clinicamentioning

confidence: 99%

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Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Ricklin

Reis

Mastellos

et al. 2016

Immunological Reviews

349

295

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Summary As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.

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Section: Too Much Too Little: Disturbed C3 Balance and Its Clinical mentioning

confidence: 99%

Section: Too Much Too Little: Disturbed C3 Balance and Its Clinicamentioning

confidence: 99%

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Ricklin

Reis

Mastellos

et al. 2016

Immunological Reviews

349

295

View full text Add to dashboard Cite

show abstract

“…It has been suggested that TTP, HUS, and MPGN have the same pathological basis and are associated with similar complement activity. Although TTP is identified by the severe lack of ADAMTS13, aHUS is characterized by hyperactivation of the alternative complement pathway as a result of mutations in an effector gene (such as C3) and a regulatory gene (like CFH) (8)(9)(10)(11). Therefore, there is a possibility of interference of the complement components gene mutations and polymorphisms in the development of TTP.…”

Section: Discussionmentioning

confidence: 99%

Genetic variations of complement factor H and C3 in patients with thrombotic thrombocytopenic purpura (TTP) in northwest of Iran

Vahed¹,

Niknafs²,

Khaniani³

et al. 2017

J Nephropathol

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Background: Thrombotic thrombocytopenic purpura (TTP) is a common form of thrombotic microangiopathy. These patients have renal insufficiency as well as thrombocytopenia and microangiopathic hemolysis. Objectives: The present study was aimed to assess if TTP patients with renal failure have prompting polymorphisms in the complement system genes as seen in patients with the atypical hemolytic uremic syndrome (aHUS). Patients and Methods: Twenty TTP patients and 30 healthy individuals were included. Two single-nucleotide polymorphisms rs3753394 and rs2230199 respectively in the complement factor H (CFH) and complement component 3 (C3) genes were determined using the PCRrestriction fragment length polymorphism (RFLP) method. To evaluate the power of the associations between the polymorphisms and TTP development, odds ratios (ORs) and 95% confidence intervals (CIs) were employed. Results: In rs2230199 polymorphism, the frequency of the C and G alleles and genotype were not significantly different in case and control groups. Moreover, the frequency of T allele and CC, CT, and TT genotypes of the rs3753394 polymorphism in TTP patients were not significantly different from those in the controls, the OR of 0.77 [CI: 0.33 to 1.79] and 0.76 [CI: 0.24 to 2.38], respectively (P > 0.05). Conclusions: Based on our results, there was no significant association between the incidence of TTP and polymorphisms of the CFH and C3 genes, neither at the allele nor at the genotypic levels (P > 0.05). This finding can be affected by the limited sample size or the genetic context of the studied population. ABSTRACT Implication for health policy/practice/research/medical education:In the present study we aimed to examine the impact of the complement factor genes polymorphisms (CFH and C3 genes) in TTP patients. No significant association was found between the incidence of TTP and polymorphisms of the CFH and C3 genes, neither at the allele nor at the genotypic levels.

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“…In 111 patients the whole coding region of the gene encoding FHR-5 (CFHR5; OMIM# 608593) was screened by direct bidirectional DNA sequencing, as described in the case of further disease-associated genes (CFH, CFI, CD46, THBD, CFB, C3) that were sequenced also (44). No DNA samples were available from the remaining 9 patients.…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

CFHR5 Genetic Variations and Serum Levels in Patients with Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

Garam¹,

Cserhalmi²,

Prohászka³

et al. 2020

Preprint

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Background: Factor H-related-5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement and follow-up data.Results: 120 patients with a histologically-proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger-sequencing, and selected mutants were studied as recombinant proteins in ELISA and SPR.Eight relevant CFHR5 variations in 14 patients (11.7%) were observed, 5 of them identified as pathogenic for C3G. The FHR-5G278S and FHR-5R356H mutations altered the interaction of FHR-5 with C3b, when compared to the FHR-5WT. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period, furthermore, it showed clear association with signs of hypocomplementemia and clinically meaningful clusters.Conclusions: Our observations support the hypothesis that FHR-5 protein and its genetic alterations play a role in the pathogenesis of IC-MPGN/C3G.

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Genetic analysis and functional characterization of novel mutations in a series of patients with atypical hemolytic uremic syndrome

Cited by 30 publications

References 67 publications

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Genetic variations of complement factor H and C3 in patients with thrombotic thrombocytopenic purpura (TTP) in northwest of Iran

CFHR5 Genetic Variations and Serum Levels in Patients with Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

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