Abstract
Atypical hemolytic uremic syndrome (aHUS) is a severe renal disorder that is associated with mutations in genes encoding proteins of the alternative complement pathway. Previously, we identified pathogenic variations in genes encoding complement regulators (CFH, CFI and MCP) in our aHUS cohort. In this study, we screened for mutations in the alternative pathway regulator CFHR5 in 65 aHUS patients by means of PCR on genomic DNA and sequence analysis. Potential pathogenicity of genetic alterations was determined by published data on CFHR5 variants, evolutionary conservation and in silico mutation prediction programs. Detection of serum CFHR5 was performed by western blot analysis and enzyme-linked immunosorbent assay. A potentially pathogenic sequence variation was found in CFHR5 in three patients (4.6%). All variations were located in short consensus repeats that might be involved in binding to C3b, heparin or C-reactive protein. The identified CFHR5 mutations require functional studies to determine their relevance to aHUS, but they might be candidates for an altered genetic profile predisposing to the disease.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Boyce, T. G., Swerdlow, D. L., Griffin, P. M. Escherichia coli O157:H7 and the hemolytic-uremic syndrome. N. Engl. J. Med. 333, 364–368 (1995).
Kaplan, B. S., Meyers, K. E., Schulman, S. L. The pathogenesis and treatment of hemolytic uremic syndrome. J. Am. Soc. Nephrol. 9, 1126–1133 (1998).
Noris, M., Brioschi, S., Caprioli, J., Todeschini, M., Bresin, E., Porrati, F. et al. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362, 1542–1547 (2003).
Caprioli, J., Noris, M., Brioschi, S., Pianetti, G., Castelletti, F., Bettinaglio, P. et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108, 1267–1279 (2006).
Fremeaux-Bacchi, V., Dragon-Durey, M. A., Blouin, J., Vigneau, C., Kuypers, D., Boudailliez, B. et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J. Med. Genet. 41, e84 (2004).
Westra, D., Volokhina, E., van der Heijden, E., Vos, A., Huigen, M., Jansen, J. et al. Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS). Nephrol. Dial Transplant. 25, 2195–2202 (2010).
Goicoechea de, J. E., Harris, C. L., Esparza-Gordillo, J., Carreras, L., Arranz, E. A., Garrido, C.A et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc. Natl Acad. Sci. USA 104, 240–245 (2007).
Fremeaux-Bacchi, V., Miller, E. C., Liszewski, M. K., Strain, L., Blouin, J., Brown, A. L. et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112, 4948–4952 (2008).
Delvaeye, M., Noris, M., De, V.A., Esmon, C.T., Esmon, N.L., Ferrell, G. et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 361, 345–357 (2009).
Jozsi, M., Licht, C., Strobel, S., Zipfel, S. L., Richter, H., Heinen, S. et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111, 1512–1514 (2008).
Noris, M., Remuzzi, G. Atypical hemolytic-uremic syndrome. N. Engl. J. Med. 361, 1676–1687 (2009).
McRae, J. L., Cowan, P. J., Power, D. A., Mitchelhill, K. I., Kemp, B. E., Morgan, B. P. et al. Human factor H-related protein 5 (FHR-5). A new complement-associated protein. J. Biol. Chem. 276, 6747–6754 (2001).
Murphy, B., Georgiou, T., Machet, D., Hill, P., McRae, J. Factor H-related protein-5: a novel component of human glomerular immune deposits. Am. J. Kidney. Dis. 39, 24–27 (2002).
McRae, J. L., Duthy, T. G., Griggs, K. M., Ormsby, R. J., Cowan, P. J., Cromer, B. A. et al. Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein. J. Immunol 174, 6250–6256 (2005).
Monteferrante, G., Brioschi, S., Caprioli, J., Pianetti, G., Bettinaglio, P., Bresin, E. et al. Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome. Mol. Immunol. 44, 1704–1708 (2007).
Abrera-Abeleda, M. A., Nishimura, C., Smith, J. L., Sethi, S., McRae, J. L., Murphy, B. F. et al. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J. Med. Genet. 43, 582–589 (2006).
Gale, D. P., de Jorge, E. G., Cook, H. T., Martinez-Barricarte, R., Hadjisavvas, A., McLean, A. G. et al. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376, 794–801 (2010).
Narendra, U., Pauer, G. J., Hagstrom, S. A. Genetic analysis of complement factor H related 5, CFHR5, in patients with age-related macular degeneration. Mol. Vis. 15, 731–736 (2009).
Skerka, C., Zipfel, P. F. Complement factor H related proteins in immune diseases. Vaccine 26 (Suppl 8), I9–14 (2008).
Gale, D. P., Pickering, M. C. Regulating complement in the kidney: insights from CFHR5 nephropathy. Dis. Model Mech. 4, 721–726 (2011).
Nurnberger, J., Philipp, T., Witzke, O., Opazo, S.A., Vester, U., Baba, H.A. et al. Eculizumab for atypical hemolytic-uremic syndrome. N. Engl. J. Med. 360, 542–544 (2009).
Maga, T. K., Nishimura, C. J., Weaver, A. E., Frees, K. L., Smith, R. J. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum. Mutat. 31, E1445–E1460 (2010).
Caprioli, J., Castelletti, F., Bucchioni, S., Bettinaglio, P., Bresin, E., Pianetti, G. et al. Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum. Mol. Genet. 12, 3385–3395 (2003).
Esparza-Gordillo, J., Goicoechea de, J. E., Buil, A., Carreras, B. L., Lopez-Trascasa, M., Sanchez-Corral, P. et al. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum. Mol. Genet. 14, 703–712 (2005).
Acknowledgements
We would like to thank patients, their parents and their physicians for their participation in this study, in particular Dr van Son (Groningen, The Netherlands). We also thank Mitali Patel (CCIR, London, United Kingdom) for helping with the MLPA. This work was partially supported by the Dutch Kidney Foundation (C09.2313, KBSO 07.0004, and KBSO 09.0008) and the Wellcome Trust (WT082291MA).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Westra, D., Vernon, K., Volokhina, E. et al. Atypical hemolytic uremic syndrome and genetic aberrations in the complement factor H-related 5 gene. J Hum Genet 57, 459–464 (2012). https://doi.org/10.1038/jhg.2012.57
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2012.57
Keywords
This article is cited by
-
Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy
Blood Cancer Journal (2023)
-
Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome
Pediatric Nephrology (2023)
-
Whole exome sequencing identifies monogenic forms of nephritis in a previously unsolved cohort of children with steroid-resistant nephrotic syndrome and hematuria
Pediatric Nephrology (2022)
-
Thrombotic microangiopathy in a patient with eosinophilic granulomatosis with polyangiitis: case-based review
Rheumatology International (2019)
-
Role of complement in the pathogenesis of thrombotic microangiopathies
memo - Magazine of European Medical Oncology (2018)
