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

Abstract

Mutations in complement factor H (HF1) gene have been reported in non-Shiga toxin-associated and diarrhoea-negative haemolytic uraemic syndrome (D-HUS). We analysed the complete HF1 in 101 patients with HUS, in 32 with thrombotic thrombocytopenic purpura (TTP) and in 106 controls to evaluate the frequency of HF1 mutations, the clinical outcome in mutation and non-mutation carriers and the role of HF1 polymorphisms in the predisposition to HUS. We found 17 HF1 mutations (16 heterozygous, one homozygous) in 33 HUS patients. Thirteen mutations were located in exons XXII and XXIII. No TTP patient carried HF1 mutations. The disease manifested earlier and the mortality rate was higher in mutation carriers than in non-carriers. Kidney transplants invariably failed for disease recurrences in patients with HF1 mutations, while in non-mutated patients half of the grafts were functioning after 1 year. Three HF1 polymorphic variants were strongly associated with D-HUS: -257T (promoter region), 2089G (exonXIV, silent) and 2881T (963Asp, SCR16). The association was stronger in patients without HF1 mutations. Two or three disease-associated variants led to a higher risk of HUS than a single one. Analysis of available relatives of mutated patients revealed a penetrance of 50%. In 5/9 families the proband inherited the mutation from one parent and two disease-associated variants from the other, while unaffected carriers inherited the protective variants. In conclusion HF1 mutations are frequent in patients with D-HUS (24%). Common polymorphisms of HF1 may contribute to D-HUS manifestation in subjects with and without HF1 mutations.

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

“…A combination of CFH and MCP polymorphic variants and environmental triggers has been shown to concur to aHUS penetrance in individuals with complement gene mutations. 3,[22][23][24][25] The unaffected carrier has the same genetic risk as his sister, because they share the MCPggaac risk haplotype on the chromosome with the duplication, but his sister, at the time of disease onset, was taking contraceptive pills, a known aHUS precipitant. 1 The unaffected carrier is 16 years old, and he may still be at risk of developing the disease on exposure to environmental trigger(s) that will activate complement and/or the endothelium.…”

A common haplotype in the complement regulatory gene factor H ( HF1/CFH ) predisposes individuals to age-related macular degeneration

“…HF1 variants with more substantial effects are implicated in earlier-onset, severe diseases, such as atypical hemolytic uremic syndrome (aHUS) (40,41,(44)(45)(46). HF1 mutations that lead to aHUS are typically missense mutations that limit the inhibitory functions of FH1.…”

“…HF1 mutations that lead to aHUS are typically missense mutations that limit the inhibitory functions of FH1. Although putative disease-causing mutations have been identified in only Ϸ25-35% of aHUS patients after complete screening of HF1 (44), a disease-associated haplotype defined by variants Ϫ257CϾT (promoter), A473A (exon 13), and D936E (exon 18) predominates in aHUS patients without identifiable disease-causing mutations (44). The at-risk haplotype in aHUS does not overlap with that of AMD and͞or MPGN.…”

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

“…However, uncontrolled activation results in collateral damage to surrounding host tissues. Organ damage from alternative complement dysregulation occurs in several renal diseases including atypical hemolytic uremic syndrome (aHUS) (233)(234)(235)(236)(237)(238)(239) and membranoproliferative glomerulonephritis type II (MPGNII) (240,241). In aHUS, widespread blood clot formation and reactive endothelial cell proliferation in small blood vessels can lead to acute renal failure.…”