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Pathogenic gain-of-function variants in complement Factor B were identified as causative of atypical Hemolytic Uremic syndrome (aHUS) in 2007. These mutations generate a reduction on the plasma levels of complement C3. A four-month-old boy was diagnosed with hypocomplementemic aHUS in May 2000, and he suffered seven recurrences during the following three years. He developed a severe hypertension which required 6 anti-hypertensive drugs and presented acrocyanosis and several confusional episodes. Plasma infusion or exchange, and immunosuppressive treatments did not improve the clinical evolution, and the patient developed end-stage renal disease at the age of 3 years. Hypertension and vascular symptoms persisted while he was on peritoneal dialysis or hemodialysis, as well as after bilateral nephrectomy. C3 levels remained low, while C4 levels were normal. In 2005, a heterozygous gain-of-function mutation in Factor B (K323E) was found. A combined liver and kidney transplantation (CLKT) was performed in March 2009, since there was not any therapy for complement inhibition in these patients. Kidney and liver functions normalized in the first two weeks, and the C3/C4 ratio immediately after transplantation, indicating that the C3 activation has been corrected. After remaining stable for 4 years, the patient suffered a B-cell non-Hodgkin lymphoma that was cured by chemotherapy and reduction of immunosuppressive drugs. Signs of liver rejection with cholangitis were observed a few months later, and a second liver graft was done 11 years after the CLKT. One year later, the patient maintains normal kidney and liver functions, also C3 and C4 levels are within the normal range. The 12-year follow-up of the patient reveals that, in spite of severe complications, CLKT was an acceptable therapeutic option for this aHUS patient. [ABSTRACT FROM AUTHOR]

Dysregulation of the alternative complement pathway is a major pathogenic mechanism in two rare renal diseases: atypical haemolytic uraemic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN). We report on a 66-year-old male with chronic hepatitis C virus (HCV) infection and a combined liver–kidney transplant that was diagnosed with MPGN at the age of 63 years and a 5-year-old boy who presented with aHUS at the age of 21 months following a Streptococcus pneumoniae infection. Both patients carried similar frameshift variants in the complement CFHR5 gene that segregate with reduced levels of factor H–related 5 (FHR-5). We conclude that low FHR-5 levels may predispose to viral and bacterial infections that then trigger different renal phenotypes. [ABSTRACT FROM AUTHOR]

Dysregulation of the complement alternative pathway (AP) is a major pathogenic mechanism in atypical hemolytic-uremic syndrome (aHUS). Genetic or acquired defects in factor H (FH), the main AP regulator, are major aHUS drivers that associate with a poor prognosis. FH activity has been suggested to be downregulated by homologous FH-related (FHR) proteins, including FHR-3 and FHR-1. Hence, their relative levels in plasma could be disease-relevant. The genes coding for FH, FHR-3, and FHR-1 (CFH, CFHR3, and CFHR1, respectively) are polymorphic and located adjacent to each other on human chromosome 1q31.3. We have previously shown that haplotype CFH(H3)-CFHR3*B-CFHR1*B associates with aHUS and reduced FH levels. In this study, we used a specific enzyme-linked immunosorbent assay to quantify FHR-3 in plasma samples from controls and patients with aHUS genotyped for the three known CFHR3 alleles (CFHR3*A, CFHR3*B, and CFHR3*Del). In the 218 patients carrying at least one copy of CFHR3, significant differences between CFHR3 genotype groups were found, with CFHR3*A/Del patients having the lowest FHR-3 concentration (0.684-1.032 µg/mL), CFHR3*B/Del and CFHR3*A/A patients presenting intermediate levels (1.437-2.201 µg/mL), and CFHR3*A/B and CFHR3*B/B patients showing the highest concentration (2.330-4.056 µg/mL) (p < 0.001). These data indicate that CFHR3*A is a low-expression allele, whereas CFHR3*B, associated with increased risk of aHUS, is a high-expression allele. Our study reveals that the aHUS-risk haplotype CFH(H3)-CFHR3*B-CFHR1*B generates twofold more FHR-3 than the non-risk CFH(H1)-CFHR3*A-CFHR1*A haplotype. In addition, FHR-3 levels were higher in patients with aHUS than in control individuals with the same CFHR3 genotype. These data suggest that increased plasma levels of FHR-3, altering the balance between FH and FHR-3, likely impact the FH regulatory functions and contribute to the development of aHUS. [ABSTRACT FROM AUTHOR]

Complement alternative pathway dysregulation seems to be the pathophysiological basis of Dense Deposit Disease (DDD). Here, we describe a monoclonal anti-factor H (FH) autoantibody in a woman diagnosed with DDD with a monoclonal gammapathy. Enzyme-linked immunosorbent assays evidenced the presence of anti-FH antibodies in the patient's serum and showed that they were associated with the monoclonal IgG-λ fraction. These autoantibodies recognize the N-terminal region of FH and interfere with its regulatory function. In summary, in the DDD patient described here, the activation of complement alternative pathway was favoured by the presence of anti-FH autoantibodies that recognize the regulatory region of this protein and impede its function and which could ultimately cause the glomerulopathy. [ABSTRACT FROM PUBLISHER]

Keywords: complement; factor H; factor H-related protein 3; CFHR3 gene; atypical hemolytic-uremic syndrome Complement, factor H, factor H-related protein 3, CFHR3 gene, atypical hemolytic-uremic syndrome. [Extracted from the article]

Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy affecting the renal microvasculature and is associated with complement dysregulation caused by mutations or autoantibodies. Disease penetrance and severity is modulated by inheritance of “risk” polymorphisms in the complement genes MCP , CFH and CFHR1 . We describe the prevalence of mutations, the frequency of risk polymorphisms and the occurrence of anti-FH autoantibodies in a Spanish aHUS cohort ( n = 367). We also report the identification of a polymorphism in CFHR3 (c.721C>T; rs379370) that is associated with increased risk of aHUS (OR = 1.78; CI 1.22–2.59; p = 0.002), and is most frequently included in an extended risk haplotype spanning the CFH-CFHR3-CFHR1 genes. This extended haplotype integrates polymorphisms in the promoter region of CFH and CFHR3 , and is associated with poorer evolution of renal function and decreased FH levels. The CFH-CFHR3-CFHR1 aHUS-risk haplotype seems to be the same as was previously associated with protection against meningococcal infections, suggesting that the genetic variability in this region is limited to a few extended haplotypes, each with opposite effects in various human diseases. These results suggest that the combination of quantitative and qualitative variations in the complement proteins encoded by CFH , CFHR3 and CFHR1 genes is key for the association of these haplotypes with disease. [ABSTRACT FROM AUTHOR]

Abstract: Age-related macular degeneration (AMD) and membranoproliferative glomerulonephritis type II (MPGN2) are dense deposit diseases that share a genetic association with complement genes and have complement proteins as important components of the dense deposits. Here, we present the case of a 64-year-old smoker male who developed both AMD and MPGN2 in his late 50s. The patient presented persistent low plasma levels of C3, factor H levels in the lower part of the normal range and C3NeF traces. Genetic analyses of the CFH, CFB, C3, CFHR1-CFHR3 and LOC387715/HTRA1 genes revealed that the patient was heterozygote for a novel missense mutation in exon 9 of CFH (c.1292 G>A) that results in a Cys431Tyr substitution in SCR7 of the factor H protein. In addition, he was homozygote for the His402 CFH allele, heterozygote for the Ser69 LOC387715 allele, homozygote for the Arg32 (BFS) CFB allele, heterozygote for the Gly102 (C3F) C3 allele and carried no deletion of the CFHR1/CFHR3 genes. Proteomic and functional analyses indicate absence in plasma of the factor H allele carrying the Cys431Tyr mutation. As a whole, these data recapitulate a prototypical complement genetic profile, including a partial factor H deficiency and the presence of major risk factors for AMD and MPGN2, which support the hypothesis that these dense deposit diseases have a common pathogenic mechanism involving dysregulation of the alternative pathway of complement activation. [Copyright &y& Elsevier]

Factor H is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma and in the protection of bystander host cells and tissues from damage by complement activation. Genetic and structural data generated during recent years have been instrumental to delineate the functional domains responsible for these regulatory activities in factor H, which is helping to understand the molecular basis underlying the different pathologies associated to factor H. This review summarises our current knowledge of the role of factor H in health and disease. [Copyright &y& Elsevier]