The Factor H protein family: The switchers of the complement alternative pathway

Lucientes, Laura; Márquez-Tirado, Bárbara; Jorge, Elena Goicoechea de

doi:10.1111/imr.13166

Cited by 31 publications

(23 citation statements)

References 145 publications

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“…( 30 ) failed to find a significant association between rare variants in CFHR5 and aHUS. Among the FHR proteins, only FHR5, like FH, has FI-dependent cofactor activity, leading to C3b inactivation, and C3 convertase decay accelerating activity ( 48 ), but these activities have been observed in the fluid phase only at higher than physiological concentrations ( 49 , 50 ). On the other hand, FHR5 has been shown to specifically interact with C3b, heparin and other cellular and extracellular ligands through its central SCR3-7, suggesting it may carry out local cell and tissue activity ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

An ex vivo test to investigate genetic factors conferring susceptibility to atypical haemolytic uremic syndrome

Gastoldi

Aiello²,

Galbusera³

et al. 2023

Front. Immunol.

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IntroductionComprehensive genetic analysis is essential to clinical care of patients with atypical haemolytic uremic syndrome (aHUS) to reinforce diagnosis, and to guide treatment. However, the characterization of complement gene variants remains challenging owing to the complexity of functional studies with mutant proteins. This study was designed: 1) To identify a tool for rapid functional determination of complement gene variants; 2) To uncover inherited complement dysregulation in aHUS patients who do not carry identified gene variants.MethodsTo address the above goals, we employed an ex-vivo assay of serum-induced C5b-9 formation on ADP-activated endothelial cells in 223 subjects from 60 aHUS pedigrees (66 patients and 157 unaffected relatives).ResultsSera taken from all aHUS patients in remission induced more C5b-9 deposition than control sera, independently from the presence of complement gene abnormalities. To avoid the possible confounding effects of chronic complement dysregulation related to aHUS status, and considering the incomplete penetrance for all aHUS-associated genes, we used serum from unaffected relatives. In control studies, 92.7% of unaffected relatives with known pathogenic variants exhibited positive serum-induced C5b-9 formation test, documenting a high sensitivity of the assay to identify functional variants. The test was also specific, indeed it was negative in all non-carrier relatives and in relatives with variants non-segregating with aHUS. All but one variants in aHUS-associated genes predicted in-silico as likely pathogenic or of uncertain significance (VUS) or likely benign resulted as pathogenic in the C5b-9 assay. At variance, variants in putative candidate genes did not exhibit a functional effect, with the exception of a CFHR5 variant. The C5b-9 assay in relatives was helpful in defining the relative functional effect of rare variants in 6 pedigrees in which the proband carried more than one genetic abnormality. Finally, for 12 patients without identified rare variants, the C5b-9 test in parents unmasked a genetic liability inherited from an unaffected parent.DiscussionIn conclusion, the serum-induced C5b-9 formation test in unaffected relatives of aHUS patients may be a tool for rapid functional evaluation of rare complement gene variants. When combined with exome sequencing the assay might be of help in variant selection, to identify new aHUS-associated genetic factors.

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Section: Discussionmentioning

confidence: 99%

An ex vivo test to investigate genetic factors conferring susceptibility to atypical haemolytic uremic syndrome

Gastoldi

Aiello²,

Galbusera³

et al. 2023

Front. Immunol.

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“…Bei Faktor H ist meist die C-terminale Domäne (SCR 19/20, s. ▶ Abb. 2) betroffen, die zu einem Verlust der Bindungsfähigkeit und Regulation von CFH an Endotheloberflächen führt [1]. Dadurch kommt es zu einer unzureichenden Hemmung einer Komplementaktivierung insbesondere auf Endothelzellen der Niere und zur Ausbildung des MAC.…”

Section: Primär üBeraktiviertes Komplementsystemunclassified

Nierenerkrankungen mit Beteiligung des Komplementsystems

Häffner

2024

Pädiatrie up2date

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“…The functions of CFHR1–5 proteins are becoming better understood. As suggested already a long time ago (10) the CFHRs are known to promote complement activity by competing with the master inhibitor CFH (6). Genetic variants of CFH and CFHR1–5 have been linked to the pathogenesis of some kidney diseases, such as C3 glomerulopathy (11), atypical hemolytic uremic syndrome (12,13) and IgA nephropathy (14).…”

Section: Introductionmentioning

confidence: 96%

“…In our recent study (2), we could not replicate the LIMS1 deletion association in the set of 1025 Finnish kidney transplantation patients and donors, but instead reported an association between CFHR locus deletion and graft rejection. The CFHR locus contains genes encoding for CFH , a major regulator of the alternative pathway (AP) of complement activation, and a set of related genes, CFHR1–5 (2,6). CFH inhibits AP activation both in body fluids and on cell surfaces.…”

Section: Introductionmentioning

confidence: 99%

The impact of complement factor H-related protein gene deletions on kidney transplantation

Salla,

Inkeri,

Ilkka

et al. 2024

Preprint

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We recently reported that a homozygous deletion in the complement factor H related (CFHR) protein gene locus predisposed kidney transplant patients to allograft rejection. As donors carried normal functional genes in the locus, the susceptibility may have resulted from alloimmune reaction to CFHR proteins. However, we found no evidence for anti-CFH response in the patients. It is therefore possible that the CFHR gene deletions and consequent protein deficiencies as such affect the rejection risk. Using multiplex ligation-dependent probe amplification method and genome sequencing, we confirmed that all 15 patients homozygous for rs7542235 GG, a SNP tagging the CFHR3─1 deletion had deletions of various sizes that invariably encompassed the whole of CFHR1 gene. The lack of CFHR1 protein in patient plasma samples was also demonstrated by Western blotting. Plasma proteomics analyses of biobank samples demonstrated that rs7542235 allele G associates with significantly changed expression levels of 23 proteins (FDR <0.010). These proteins are involved in various pathways, including regulation of alloimmune response and their roles in transplantation outcome merit further studies. Although CFHR gene abnormalities have been associated with kidney diseases, we observed no clinical characteristics shared by or enriched in patients homozygous for CFHR1 deletion. This suggests that the deletion as such was not enriched in a baseline disease in this subgroup with a high risk for rejection. To conclude, the different deletion types found in patients shared the complete deletion of the CFHR1 gene pointing to its primary role. Plasma proteomics studies show that deletion-tagging allele is associated with altered expression of CFH/CFHR proteins.

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The Factor H protein family: The switchers of the complement alternative pathway

Cited by 31 publications

References 145 publications

An ex vivo test to investigate genetic factors conferring susceptibility to atypical haemolytic uremic syndrome

An ex vivo test to investigate genetic factors conferring susceptibility to atypical haemolytic uremic syndrome

Nierenerkrankungen mit Beteiligung des Komplementsystems

The impact of complement factor H-related protein gene deletions on kidney transplantation

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