Background Sequence analysis of the regulators of complement activation (RCA) cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH) and the genes for the five factor H-related proteins (CFHL1–5; aliases CFHR1–5). CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS). The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS. Methods and Findings In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1–21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A) that has been previously described in association with aHUS. Conclusions CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene.
References
[1]
Warwicker P, Goodship THJ, Donne RL, Pirson Y, Nicholls A, et al. (1998) Genetic studies into inherited and sporadic haemolytic uraemic syndrome. Kidney Int 53: 836–844.
[2]
Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, et al. (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci U S A 100: 12966–12971.
[3]
Diaz-Guillen MA, Rodriguez de Cordoba S, Heine-Suner D (1999) A radiation hybrid map of complement factor H and factor H-related genes. Immunogenetics 49: 549–552.
[4]
Male DA, Ormsby RJ, Ranganathan S, Giannakis E, Gordon , et al. (2000) Complement factor H: Sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes. Mol Immunol 37: 41–52.
[5]
Zipfel PF, Jokiranta TS, Hellwage J, Koistinen V, Meri S (1999) The factor H protein family. Immunopharmacology 42: 53–60.
[6]
Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, et al. (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition. Am J Hum Genet 68: 485–490.
[7]
Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, Vera M, Lopez-Trascasa M, et al. (2001) Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet 68: 478–484.
[8]
Caprioli J, Bettinaglio P, Zipfel PF, Amadei B, Daina E, et al. (2001) The molecular basis of familial hemolytic uremic syndrome: Mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol 12: 297–307.
[9]
Neumann HP, Salzmann M, Bohnert-Iwan B, Mannuelian T, Skerka C, et al. (2003) Haemolytic uraemic syndrome and mutations of the factor H gene: A registry-based study of German speaking countries. J Med Genet 40: 676–681.
[10]
Heinen S, Sanchez-Corral P, Jackson MS, Strain L, Goodship JA, et al. (2006) De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum Mut 27: 292–293.
[11]
Lupski JR, Stankiewicz P (2005) Genomic disorders: Molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet 1: e49.
[12]
Feifel E, Prodinger WM, Molgg M, Schwaeble W, Schonitzer D, et al. (1992) Polymorphism and deficiency of human factor H-related proteins p39 and p37. Immunogenetics 36: 104–109.
[13]
Farr MJ, Roberts S, Morley AR, Dewar PJ, Roberts DF, et al. (1975) The haemolytic uraemic syndrome—A family study. Q J Med 44: 161–188.
[14]
Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P (2004) The human complement factor H: Functional roles, genetic variations and disease associations. Mol Immunol 41: 355–367.
[15]
Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, et al. (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30: e57.
[16]
Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, et al. (2006) Outcome of renal transplantation in patients with non-shiga toxin-associated hemolytic uremic syndrome: Prognostic significance of genetic background. Clin J Am Soc Nephrol 1: 88–99.
[17]
Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, et al. (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308: 421–424.
[18]
Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308: 419–421.
[19]
Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308: 385–389.
[20]
Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102: 7227–7232.
[21]
Abrera-Abeleda MA, Nishimura C, Smith JL, Sethi S, McRae JL, et al. (2006) 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.
