Novel duplication of the FHRs dimerization domain associated with C3G

Tortajada, Agustín; Gutiérrez-Tenorio, Josué; González, Ana Saiz; Letosa, R. Marcén; Bouthelier, Antonio; Sánchez-Corral, Pilar; Goicoechea, Elena; Córdoba, Santiago Rodrı́guez de

doi:10.1016/j.molimm.2017.06.169

Cited by 3 publications

(4 citation statements)

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“…One patient diagnosed with C3 glomerulopathy has in one CFHR1 allele a duplication, which includes the CFHR1 promoter and exons i-iii, resulting in a mutant gene with two transcription start sites (Figure 4B). 66 The upstream promoter generates a longer transcript, which codes FHR1 1-2 FHR1. The mutant proteins with two multimerization segments form large oligomeric complexes with other FHR proteins, which enhance hemolysis (Supplemental Table 1).…”

Section: Insertional Mutagenesis Of Intragenic Segmentsmentioning

confidence: 99%

“…In physiologic settings, FHR proteins and also Factor H adapt various conformations and can form dimers, tetramers, or multimers (Figure 5A). 58,66,67,[111][112][113][114][115] Such multimers enhance regulatory action; for example, Factor H mini-variants, which are linked via an FHR1 multimerization region, are more potent in complement control. 116,117 For both FHR1 mutants with duplicated interaction segments, 67,68 for the FHR1-FHR5, 65 and also for the FHR2::FHR5 66 hybrid formation of large oligomeric complexes is reported, which enhance complement activity.…”

Section: Fhr Proteins Form Multimers That Show a Preference For Interaction Partnersmentioning

confidence: 99%

“…Apparently, payload composition and the combinations of functionally distinct FHR proteins influence oligomer function (Figures 5, C and D and 6). [65][66][67][68] FHR Proteins as Biomarkers for Diagnosis and Therapy CFHR gene variations define specific genetic forms that integrate in the overall disease spectrum of aHUS and C3 glomerulopathy. The current diagnosis for C3 glomerulopathy is on the basis of kidney biopsy specimens.…”

Section: Payload Composition Influences Oligomer Functionmentioning

confidence: 99%

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CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Zipfel

Wiech

Stea

et al. 2020

JASN

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Sequence and copy number variations in the human CFHR–Factor H gene cluster comprising the complement genes CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, and Factor H are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant CFHR genes, as well as hybrid CFHR–Factor H genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: CFHR1, CFHR3, and Factor H gene alterations combined with intact CFHR2, CFHR4, and CFHR5 genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five CFHR genes in the context of an intact Factor H gene are described in C3 glomerulopathy. These genetic modifications influence complement function and the interplay of the five FHR proteins with each other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology is of high interest for diagnosis and therapy.

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Section: Insertional Mutagenesis Of Intragenic Segmentsmentioning

confidence: 99%

Section: Fhr Proteins Form Multimers That Show a Preference For Interaction Partnersmentioning

confidence: 99%

Section: Payload Composition Influences Oligomer Functionmentioning

confidence: 99%

See 1 more Smart Citation

CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Zipfel

Wiech

Stea

et al. 2020

JASN

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“…The authors proposed that multimerization of FHR-1 strongly inhibits FH binding to certain cell surfaces, but not to endothelial cells, the target surface in aHUS. A different FHR-1 protein containing two copies of domains CCPs 1–2 has been described in another Spanish patient with a C3G clinical phenotype, but further characterization of this duplicated FHR-1 (containing seven domains) has not been provided ( 180 ).…”

Section: Disease Associationsmentioning

confidence: 99%

Self-Damage Caused by Dysregulation of the Complement Alternative Pathway: Relevance of the Factor H Protein Family

et al. 2018

Self Cite

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The alternative pathway is a continuously active surveillance arm of the complement system, and it can also enhance complement activation initiated by the classical and the lectin pathways. Various membrane-bound and plasma regulatory proteins control the activation of the potentially deleterious complement system. Among the regulators, the plasma glycoprotein factor H (FH) is the main inhibitor of the alternative pathway and its powerful amplification loop. FH belongs to a protein family that also includes FH-like protein 1 and five factor H-related (FHR-1 to FHR-5) proteins. Genetic variants and abnormal rearrangements involving the FH protein family have been linked to numerous systemic and organ-specific diseases, including age-related macular degeneration, and the renal pathologies atypical hemolytic uremic syndrome, C3 glomerulopathies, and IgA nephropathy. This review covers the known and recently emerged ligands and interactions of the human FH family proteins associated with disease and discuss the very recent experimental data that suggest FH-antagonistic and complement-activating functions for the FHR proteins.

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