A retrospective genetic analysis in our aHUS cohort (<i>n</i>=513) using multiple ligation probe amplification uncovered nine unrelated patients carrying a genetic abnormality in the complement factor H related 1 gene (<i>CFHR1</i>) that originates by recurrent gene conversion events between the <i>CFH</i> and <i>CFHR1</i> genes.
Our data suggest a complex matrix of interactions between FHR1-FHR3 deletion, immunomodulation and anti-FH autoantibodies in the aetiopathogenesis of aHUS.
Genetic analysis showed large heterozygous deletion encompassing the entire CFHR1 and CFHR3, a finding previously associated with patients presenting atypical hemolytic-uremic syndrome (aHUS).
We observed a similar extent of autoantibody binding to the aHUS-specific epitope aa1177-1191 on FH and aa276-290 on CFHR1, despite seven of our patients being deficient for CFHR1.
<i>CFHR1</i> deficiency was significantly associated with an increased risk of aHUS (odds ratio (OR) = 3.61, 95% confidence interval (95% CI), 1.96, 6.63, <i>p</i> < 0.001), while no association was demonstrated in individuals with only <i>CFHR1/R3</i> deficiency (OR = 1.32, 95% CI, 0.50, 3.50, <i>p</i> = 0.56).
Cumulatively, our data suggest that association of CFHR1 deficiency with autoimmune aHUS could be due to the structural difference between CFHR1 and the autoantigenic CFH epitope, suggesting a novel explanation for CFHR1 deficiency in the pathogenesis of autoimmune aHUS.
A novel atypical hemolytic uremic syndrome-associated hybrid CFHR1/CFH gene encoding a fusion protein that antagonizes factor H-dependent complement regulation.
No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients.
The CFH-CFHR3-CFHR1aHUS-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.
Genetic abnormalities in the complement system, proteins including CFH, CFI, CFB, C3, CFHR1/3 and MCP (CD46) lead to uncontrolled complement activation in aHUS.
The following tests were performed in all six patients: serum C3 and C4 levels, ADAMTS13 activity, CFH levels and anti-CFH autoantibodies and genetic screening for CFH, MCP, CFI, C3 and CFHR1-3 mutations and risk haplotypes associated with aHUS.
Mutations in complement factor H (CFH), factor I (CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H (αFH) with or without a homozygous deletion in CFH-related protein 1 and 3 (∆CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS).
Autoantibodies to complement inhibitor factor H (FH), particularly in association with deletions of the gene coding for FH-related protein 1 (CFHR1), are associated with aHUS.
The hybrid CFH/CFHR1 protein has an altered C3b/C3d binding, is incapable to protect cells from complement attack and is directly implicated in aHUS pathogenesis.
The case of a 12-year-old with a hybrid CFH/CFHL1 gene and atypical hemolytic uremic syndrome (aHUS) that had previously developed native kidney and then renal allograft loss is reported.
The autoimmune form of atypical hemolytic uremic syndrome (HUS) is characterized by circulating autoantibodies against the complement regulator factor H, and is often associated with deficiency of the factor H-related proteins CFHR1 and CFHR3.
In this report, we describe successful deceased donor renal transplantation in a case of CFH-autoantibody associated aHUS with combined CFHR1 and 3 deficiency in addition to the CFH sequence variant, (cG2850T, pGln950His).
We also report the characterization of a novel CFHR1 polymorphism, resulting from a gene conversion event between CFH and CFHR1, which strongly associates with aHUS.