A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

Francis, Nigel J.; McNicholas, Bairbre; Awan, Atif; Waldron, Mary; Reddan, Donal; Sadlier, Denise; Kavanagh, David; Strain, Lisa; Marchbank, Kevin J.; Harris, Claire L.; Goodship, Timothy H.J.

doi:10.1182/blood-2011-03-339903

Cited by 83 publications

(70 citation statements)

References 38 publications

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“…CFH/CFHR rearrangements were associated with poor clinical prognosis and high risk of post-transplant recurrence. 13,15,16 Of relevance, in a family where two individuals have been affected by aHUS, we found a novel duplication in the CFH-CFHR genomic area. The duplication results in an additional copy of CFHR3 and the formation of an extra hybrid copy of CFHR1 derived from the fusion of the first five exons of CFHR1 and the last exon 23 of CFH.…”

Section: Discussionmentioning

confidence: 75%

“…16 In summary, we describe a new CFHR1/CFH hybrid gene that adds to previously reported genomic rearrangements in the CFH-CFHR region. [13][14][15][16] Such rearrangements are associated with post-transplant recurrence, which however, can be prevented by eculizumab prophylaxis. 16,28 Because of the unaffordable economic burden of such an expensive drug, identification of patients who are the most likely to benefit from eculizumab is mandatory.…”

Section: Discussionmentioning

confidence: 99%

“…The most frequently observed NAHR is the deletion of CFHR3-CFHR1 that is strongly associated with anti-FH autoantibodies and aHUS. 7,[10][11][12] Several hybrid genes deriving from NAHR in the CFH-CFHR region have been also identified in aHUS, [13][14][15] including hybrid CFH/CFHR1 and CFH/CFHR3 genes. Recently, a hybrid CFHR1/CFH gene that encodes a fusion protein with the first three short consensus repeats (SCRs) of FHR1 and the last two SCRs of FH has been reported in a sporadic case of aHUS.…”

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confidence: 99%

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A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

Valoti

Alberti

Tortajada

et al. 2015

Journal of the American Society of Nephrology

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Genomic aberrations affecting the genes encoding factor H (FH) and the five FH-related proteins (FHRs) have been described in patients with atypical hemolytic uremic syndrome (aHUS), a rare condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ARF. These genomic rearrangements occur through nonallelic homologous recombinations caused by the presence of repeated homologous sequences in CFH and CFHR1-R5 genes. In this study, we found heterozygous genomic rearrangements among CFH and CFHR genes in 4.5% of patients with aHUS. CFH/CFHR rearrangements were associated with poor clinical prognosis and high risk of post-transplant recurrence. Five patients carried known CFH/CFHR1 genes, but we found a duplication leading to a novel CFHR1/CFH hybrid gene in a family with two affected subjects. The resulting fusion protein contains the first four short consensus repeats of FHR1 and the terminal short consensus repeat 20 of FH. In an FH-dependent hemolysis assay, we showed that the hybrid protein causes sheep erythrocyte lysis. Functional analysis of the FHR1 fraction purified from serum of heterozygous carriers of the CFHR1/ CFH hybrid gene indicated that the FHR1/FH hybrid protein acts as a competitive antagonist of FH. Furthermore, sera from carriers of the hybrid CFHR1/CFH gene induced more C5b-9 deposition on endothelial cells than control serum. These results suggest that this novel genomic hybrid mediates disease pathogenesis through dysregulation of complement at the endothelial cell surface. We recommend that genetic screening of aHUS includes analysis of CFH and CFHR rearrangements, particularly before a kidney transplant.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

Valoti

Alberti

Tortajada

et al. 2015

Journal of the American Society of Nephrology

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“…[22][23][24][25][26] Novel genetic abnormalities of CFHR1, CFHR3, and CFHR4 and genomic rearrangement between CFH and CFHR1 have recently been described. 27,28 Incomplete penetrance of aHUS has been reported in mutation carriers, 12,[29][30][31] indicating that complement gene mutations confer predisposition to develop aHUS, with additional genetic and/or environmental hits necessary for disease manifestation. 7,32,33 In keeping with this hypothesis, patients with mutations in more than one complement gene (combined gene mutations) have been described.…”

mentioning

confidence: 99%

Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

Bresin

Rurali

Caprioli

et al. 2013

Journal of the American Society of Nephrology

322

290

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Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype-phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%-10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation.

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“…In addition, copy number variations (CNVs) in the human gene cluster that includes the five CFHR genes are defined in several human diseases including C3 glomerulopathy (C3G), [5][6][7][8][9] atypical hemolytic uremic syndrome, [10][11][12][13][14][15] deficiency of CFHR plasma proteins and factor H autoantibody positive hemolytic uremic syndrome, [16][17][18][19][20] age-related macular degeneration, [21][22][23] IgA nephropathy, 24 as well as systemic lupus erythematosus. 25 CNVs in the CFHR5 gene are identified in patients with C3G, 5-7 a devastating kidney disease characterized by C3 deposition in glomeruli.…”

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confidence: 99%

Complement Factor H-Related 5-Hybrid Proteins Anchor Properdin and Activate Complement at Self-Surfaces

Chen

Manzke

Hartmann

et al. 2015

JASN

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C3 glomerulopathy (C3G) is a severe kidney disease for which no specific therapy exists. The causes of C3G are heterogeneous, and defective complement regulation is often linked to C3G pathogenesis. Copy number variations in the complement factor H-related (CFHR) gene cluster on chromosome 1q32 and CFHR5 mutant proteins associate with this disease. Here, we identified CFHR5 as a pattern recognition protein that binds to damaged human endothelial cell surfaces and to properdin, the human complement activator. We found the two N-terminal short consensus repeat domains of CFHR5 contact properdin and mediate dimer formation. These properdin-binding segments are duplicated in two mutant CFHR5 proteins, CFHR2-CFHR5 Hyb from German patients with C3G and CFHR5 Dup from Cypriot patients with C3G. Each of these mutated proteins assembled into large multimeric complexes and, compared to CFHR5, bound damaged human cell surfaces and properdin with greater intensity and exacerbated local complement activation. This enhanced surface binding and properdin recruitment was further evidenced in the mesangia of a transplanted and explanted kidney from a German patient with a CFHR2-CFHR5 Hyb protein. Enhanced properdin staining correlated with local complement activation with C3b and C5b-9 deposition on the mesangial cell surface in vitro. This gain of function in complement activation for two disease-associated CFHR5 mutants describes a new disease mechanism of C3G, which is relevant for defining appropriate treatment options for this disorder.

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A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

Cited by 83 publications

References 38 publications

A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

Complement Factor H-Related 5-Hybrid Proteins Anchor Properdin and Activate Complement at Self-Surfaces

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