Complement Mutations in Diacylglycerol Kinase-ε–Associated Atypical Hemolytic Uremic Syndrome

Chinchilla, Daniel Sánchez; Pinto, Sheila; Höppe, Bernd; Adragna, Marta; López, Laura; Roldán, M.Luisa Justa; Pena, A De La; López-Trascasa, Margarita; Sánchez-Corral, Pilar; Córdoba, Santiago Rodrı́guez de

doi:10.2215/cjn.01640214

Cited by 68 publications

(61 citation statements)

References 33 publications

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“…31 Because we have no similar models for the calculation of the overall risk for aHUS, we have considered in this estimation the presence of mutations in additional aHUS candidate genes and the genotypes for the CFH-H3 and MCPggaac aHUS risk haplotypes. 32 We therefore gave 1 point for each additional mutation or risk polymorphism, and the sum of the codes was used as a continuous variable. In contrast with the overall AMD risk (P values), which range from 0% to 100%, the overall risks for aHUS are increasing numerals (i.e., 0, 1, 2, 3, etc.).…”

Section: Overall Genetic Risks For Ahus and Amd And Statistical Analysesmentioning

confidence: 99%

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

Recalde

Tortajada

Subias

et al. 2015

JASN

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The complement factor H (FH) mutation R1210C, which was described in association with atypical hemolytic uremic syndrome (aHUS), also confers high risk of agerelated macular degeneration (AMD) and associates with C3 glomerulopathy (C3G). To reveal the molecular basis of these associations and to provide insight into what determines the disease phenotype in FH-R1210C carriers, we identified FH-R1210C carriers in our aHUS, C3G, and AMD cohorts. Disease status, determined in patients and relatives, revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in the AMD cohort. These findings were consistent with differences in the R1210C-independent overall risk for aHUS and AMD between mutation carriers developing one pathology or the other. R1210C is an unusual mutation that generates covalent complexes between FH and HSA. Using purified FH proteins and surface plasmon resonance analyses, we demonstrated that formation of these FH-HSA complexes impairs accessibility to all FH functional domains. These data suggest that R1210C is a unique C-terminal FH mutation that behaves as a partial FH deficiency, predisposing individuals to diverse pathologies with distinct underlying pathogenic mechanisms; the final disease outcome is then determined by R1210C-independent genetic risk factors.

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Section: Overall Genetic Risks For Ahus and Amd And Statistical Analysesmentioning

confidence: 99%

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

Recalde

Tortajada

Subias

et al. 2015

JASN

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“…The penetrance of these mutations is low, and a trigger is required for the development of the disease (Noris et al 2010). Besides complement proteins, mutations in thrombomodulin and in diacylglycerol kinase ε have been described in a small cohort of aHUS patients (Delvaeye et al 2009;Lemaire et al 2013;Rodriguez de Cordoba et al 2014;Sanchez Chinchilla et al 2014). Mutations in the factor H gene (CFH) are the most prevalent genetic alterations representing ~25% of cases ).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome

Nozal

Bernabeu-Herrero

Uzonyi

et al. 2016

Molecular Immunology

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Factor H (FH) autoantibodies are present in 6-10% of atypical hemolytic uremic syndrome (aHUS) patients, most of whom have homozygous deficiency of the FH-related protein FHR-1.Although the pathogenic role of the autoantibodies is established, little is known about their molecular characteristics and changes over time. Here, we describe the specificity and other immunological features of anti-FH autoantibodies in the Spanish and Hungarian aHUS cohorts.A total of 19 patients were included and serial samples of 14 of them were available. FH autoantibodies from FHR-1 deficient patients (n=13) mainly recognized FH, its SCR19-20 fragment and FHR-1, but autoantibody specificity in patients who are homo-or heterozygous for the CFHR1 gene (n=6)

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“…A DGKE-funkciózavar nem érinti a komplementrendszer működését, ugyanakkor az endothelsejtek protrombotikus változását okozza. 2014-ben közölték, hogy egyes betegekben együtt van jelen a komplement alternatív út szabályozási zavara és a DGKE-mutáció, és a komplement-rendellenesség nagyban meghatározza a HUS megjelenésének idejét és sú-lyosságát [81]. Indokolt ezért minden korai kezdetű HUS esetén a genetikai vizsgálatokat a DGKE irányában is kiterjeszteni.…”

Section: Diacilglicerol-kináz-epszilon (Dgke)-mutációhoz Kapcsolt Husunclassified

Egészségügyi szakmai irányelv – A thromboticus thrombocytopeniás purpura (TTP) és a haemolyticus uraemiás syndroma (HUS) kezeléséről

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2017

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Complement Mutations in Diacylglycerol Kinase-ε–Associated Atypical Hemolytic Uremic Syndrome

Cited by 68 publications

References 33 publications

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome

Egészségügyi szakmai irányelv – A thromboticus thrombocytopeniás purpura (TTP) és a haemolyticus uraemiás syndroma (HUS) kezeléséről

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