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

Bresin, Elena; Rurali, Erica; Caprioli, Jessica; Sánchez-Corral, Pilar; Frémeaux‐Bacchi, Véronique; Córdoba, Santiago Rodrı́guez de; Pinto, Sheila; Goodship, Timothy H.J.; Alberti, Marta; Ribes, David; Valoti, Elisabetta; Remuzzi, Giuseppe; Noris, Marina

doi:10.1681/asn.2012090884

Cited by 319 publications

(325 citation statements)

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“…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. 3,26,27 This possibility is supported by finding that serum from this subject induced excessive C5b-9 deposition on activated endothelial cells compared with control serum.…”

Section: Discussionmentioning

confidence: 62%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…Two cousins with disease onset at the ages of 6 months and 20 years (the former also carried the CFI mutation) 3 and two patients with sporadic aHUS (onset: 1 and 22 years) had a previously described heterozygous CFH/CFHR1 hybrid gene including exons 1-21 of CFH and exons 5 and 6 of CFHR1. 13 In a sporadic patient (onset at 5 months), we found another previously reported hybrid CFH/CFHR1 14 including exons 1-22 of CFH and exon 6 of CFHR1.…”

Section: Genomic Cfh-cfhrs Rearrangementsmentioning

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: 62%

Section: Discussionmentioning

confidence: 99%

Section: Genomic Cfh-cfhrs Rearrangementsmentioning

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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“…Despite the advances in understanding aHUS genetic causes, approximately 40% of patients still do not carry mutations in CFH, MCP, CFI, CFB, C3, THBD, and DGKE or deletions/rearrangements in CFH-CFHRs region (2,3,5,7,25). To our knowledge, this is the first report describing an intronic mutation located beyond exon/intron boundaries in DGKE and in general in aHUS-associated genes.…”

Section: Discussionmentioning

confidence: 86%

“…It has a poor prognosis with approximately 60% of patients progressing to ESRD and a mortality rate between 4% and 25% (1,2). Extensive studies showed that hyperactivation of the complement alternative pathway is the main pathogenetic effector mechanism leading to endothelial damage and microvascular thrombosis in most patients with aHUS (1,2 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). These findings paved the way for complement-tailored treatments (1,11) that have led to impressive improvements in short-and long-term prognosis (12).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome

Mele¹,

Lemaire²,

Iatropoulos³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.Design, setting, participants, & measurements Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.Results Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A.G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.Conclusions This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process nextgeneration sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases.

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Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration

Ferrara

Seddon

2015

JAMA Ophthalmol

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IMPORTANCE The complement factor H R1210C rare variant confers the strongest genetic risk for age-related macular degeneration and earlier age at onset; however, its associated phenotype has not been well characterized. OBJECTIVE To describe specific fundus features of a white population with the R1210C rare variant. DESIGN, SETTING, AND PARTICIPANTS Fundus features specific for diagnosis and disease staging were retrospectively characterized by systematic review of all available fundus images for each patient, including color photography, fluorescein angiography, fundus autofluorescence, and optical coherence tomography, at a tertiary ophthalmologic referral center. For this retrospective observational study conducted from 2012 to 2014, enrolled patients with the variant and their family members without the variant were identified from the Age-Related Macular Degeneration Study for a family-based study arm. For patients with the variant but without a family member enrolled in the study, age-matched comparison individuals without the variant were selected randomly from the database. MAIN OUTCOMES AND MEASURES The presence of drusen in the macula (macular drusen score) and estimated number (total macular drusen score) were assessed. The presence of drusen in the extramacular regions (extramacular drusen score), pigmentary abnormalities, and disease staging were also evaluated. Binary logistic regression models were used to evaluate the association between rare variant status and ocular phenotypes. RESULTS Images from a total of 143 patients (283 eyes), including 62 patients with the rare variant, were analyzed. Drusen score covariates were associated with the R1210C rare variant. A larger proportion of patients carrying the variant had the highest level of macular and total macular drusen scores compared with those without the variant (57.9% vs 16.7% and 52.9% vs 14.2%, respectively; P for trend < .001 for both scores). Patients carrying the rare variant had a much greater likelihood of having advanced disease (odds ratio, 7.0; 95% CI, 3.1-16.2; P < .001). A higher prevalence of geographic atrophy was observed among patients carrying the variant (odds ratio, 13.7; 95% CI, 5.0-37.7; P < .001). CONCLUSIONS AND RELEVANCE The typical phenotype of the complement factor H R1210C rare variant is associated with extensive drusen accumulation in the macula and throughout the fundus, as well as with a high risk for having advanced disease. Better characterization of genetic profiles in age-related macular degeneration may be important for screening and future therapeutic strategies for this vision-threatening condition.

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

Cited by 319 publications

References 63 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

Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome

Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration

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