The spectrum of phenotypes caused by variants in the CFH gene

Boon, Camiel J F; Kar, N.C. van de; Klevering, B. Jeroen; Keunen, Jan E.E.; Cremers, Frans P.M.; Klaver, Caroline C.W.; Hoyng, Carel B.; Daha, Mohamed R.; Hollander, Anneke I. den

doi:10.1016/j.molimm.2009.02.013

Cited by 83 publications

(72 citation statements)

References 305 publications

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“…14 CFH protein, encoded by gene CFH, is a well known inhibitor of complement activation with a variety of functions, including competition with factor B to hinder the formation of C3 convertase, facilitation of the dissociation of C3 convertase, and support of proteolytic cleavage of C3b by factor I. 15,16 Although complement regulatory functions have been attributed to CFH, CFHR3, and CFHR1, their precise biologic roles are not identical.…”

mentioning

confidence: 99%

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Zhu

Zhai

Wang

et al. 2015

Journal of the American Society of Nephrology

127

108

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Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1Δ) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1Δ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.

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mentioning

confidence: 99%

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Zhu

Zhai

Wang

et al. 2015

Journal of the American Society of Nephrology

127

108

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“…By these mechanisms, FH downregulates the alternative complement pathway (7). Mutations, polymorphisms, and autoantibodies affecting FH, which are associated with AMD, aHUS, DDD, and other C3 glomerulopathies, influence the ability of FH to interact with C3b and/or with host cells or extracellular ligands, thus causing alterations in the activity of this important complement regulator (10)(11)(12).…”

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confidence: 99%

An Engineered Construct Combining Complement Regulatory and Surface-Recognition Domains Represents a Minimal-Size Functional Factor H

Hebecker

Alba-Domínguez

Roumenina

et al. 2013

The Journal of Immunology

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Complement is an essential humoral component of innate immunity; however, its inappropriate activation leads to pathology. Polymorphisms, mutations, and autoantibodies affecting factor H (FH), a major regulator of the alternative complement pathway, are associated with various diseases, including age-related macular degeneration, atypical hemolytic uremic syndrome, and C3 glomerulopathies. Restoring FH function could be a treatment option for such pathologies. In this article, we report on an engineered FH construct that directly combines the two major functional regions of FH: the N-terminal complement regulatory domains and the C-terminal surface-recognition domains. This minimal-size FH (mini-FH) binds C3b and has complement regulatory functions similar to those of the full-length protein. In addition, we demonstrate that mini-FH binds to the FH ligands C-reactive protein, pentraxin 3, and malondialdehyde epitopes. Mini-FH was functionally active when bound to the extracellular matrix and endothelial cells in vitro, and it inhibited C3 deposition on the cells. Furthermore, mini-FH efficiently inhibited complement-mediated lysis of host-like cells caused by a disease-associated FH mutation or by anti-FH autoantibodies. Therefore, mini-FH could potentially be used as a complement inhibitor targeting host surfaces, as well as to replace compromised FH in diseases associated with FH dysfunction.

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Section: Balkan Journal Of Medical Geneticsmentioning

confidence: 99%

“…Sometimes patients may have more than one of these conditions, suggesting common mechanisms in their pathogenesis [1]. However, there is no straightforward genotype-phenotype correlation between the CFH variants and disease [1]. It has been reported that the C allele for the CFH c.1277 T>C polymorphism increases the odds ratio of AMD up to 6-fold in different populations except the Japanese [21][22][23].…”

Section: Balkan Journal Of Medical Geneticsmentioning

confidence: 99%

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Complement Factor H Y403H Polymorphism in the Turkish Population

Arıkan

Bilgen

Keser

2010

Balkan Journal of Medical Genetics

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Complement factor H (CFH) is an important regulator protein of the alternative pathway of the complement system. The CFH mutations and polymorphisms in CFH have been associated with diseases of the kidney and eye. We investigated the allelic frequency of the most common CFH polymorphism, c.1277 T>C (Y402H), in 100 healthy Turkish volunteers from the Antalya Province by direct sequencing of the corresponding genomic region. We found a frequency of 0.65% for the T and 0.35% for the C alleles. The frequency of the TT, CT and CC genotypes was 0.40, 0.49 and 0.11% respectively. Thus, the disease-related C allele has a frequency in Turkey similar to that of Caucasian populations.

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The spectrum of phenotypes caused by variants in the CFH gene

Cited by 83 publications

References 305 publications

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

An Engineered Construct Combining Complement Regulatory and Surface-Recognition Domains Represents a Minimal-Size Functional Factor H

Complement Factor H Y403H Polymorphism in the Turkish Population

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