Effect of rare coding variants in the CFI gene on Factor I expression levels

Jong, Sarah de; Volokhina, Elena; Breuk, Anita de; Nilsson, Sara C.; Jong, Eiko K. de; Kar, Nicole C.A.J. van der; Bakker, Björn; Hoyng, Carel B.; Heuvel, Lambert P. van den; Blom, Anna M.; Hollander, Anneke I. den

doi:10.1093/hmg/ddaa114

Cited by 42 publications

(48 citation statements)

References 39 publications

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“…Furthermore, 3.2% of total patients recruited to this study ( n = 15) expressed a pathogenic or likely pathogenic CFI gene variant. The largest proportion of these patients ( n = 10) expressed the CFI p.Gly119Arg variant (NM_000204.3:c.355G>A), which has robust evidence of pathogenicity in previous studies (de Jong et al, 2020; Fremeaux‐Bacchi et al, 2013; Hallam et al, 2020; Kavanagh et al, 2015; Maga et al, 2010; van de Ven et al, 2013). Four patients expressed a rare pathogenic CFI gene variant, which also resulted in low serum FI levels in previous studies: p.Pro50Ala (Bienaime et al, 2010; Nilsson et al, 2010; Szilagyi et al, 2013), p.Ala258Thr (Alba‐Dominguez et al, 2012; Kavanagh et al, 2015; Nilsson et al, 2009; Ponce‐Castro et al, 2008; Sullivan et al, 2010; Vyse et al, 1996), p.His418Leu (Donegan et al, 2020; Nilsson et al, 2009; Vyse et al, 1996), and p.Ala431Thr (Bienaime et al, 2010).…”

Section: Discussionmentioning

confidence: 69%

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy

et al. 2021

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Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age‐related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease‐causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross‐sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype‐phenotype study was performed. Four hundred and sixty‐eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 μg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.

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Section: Discussionmentioning

confidence: 69%

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy

et al. 2021

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“…45,49,50 Genetic variants reducing CFI levels confer an increased risk of AMD, highlighting its protective role of dampening down complement. [66][67][68][69] However, in advanced AMD, this protection may be overwhelmed by the robust complement activation at the atrophic lesion area where recruited microglia/macrophages supply high levels of C3 and C1Q. FIGURE 6.…”

Section: Discussionmentioning

confidence: 99%

Differential and Altered Spatial Distribution of Complement Expression in Age-Related Macular Degeneration

Demirs

Yang

Crowley

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Dysregulation of the alternative complement pathway is a major pathogenic mechanism in age-related macular degeneration. We investigated whether locally synthesized complement components contribute to AMD by profiling complement expression in postmortem eyes with and without AMD.METHODS. AMD severity grade 1 to 4 was determined by analysis of postmortem acquired fundus images and hematoxylin and eosin stained histological sections. TaqMan (donor eyes n = 39) and RNAscope/in situ hybridization (n = 10) were performed to detect complement mRNA. Meso scale discovery assay and Western blot (n = 31) were used to measure complement protein levels. RESULTS.The levels of complement mRNA and protein expression were approximately 15-to 100-fold (P < 0.0001-0.001) higher in macular retinal pigment epithelium (RPE)/choroid tissue than in neural retina, regardless of AMD grade status. Complement mRNA and protein levels were modestly elevated in vitreous and the macular neural retina in eyes with geographic atrophy (GA), but not in eyes with early or intermediate AMD, compared to normal eyes. Alternative and classical pathway complement mRNAs (C3, CFB, CFH, CFI, C1QA) identified by RNAscope were conspicuous in areas of atrophy; in those areas C3 mRNA was observed in a subset of IBA1 + microglia or macrophages. CONCLUSIONS.We verified that RPE/choroid contains most ocular complement; thus RPE/choroid rather than the neural retina or vitreous is likely to be the key site for complement inhibition to treat GA or earlier stage of the disease. Outer retinal local production of complement mRNAs along with evidence of increased complement activation is a feature of GA.

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“… Sex/age, yr Creatinine, μmol/L MAHA Platelets, ×10 9 /L Treatment Outcome Gene/FHAA Variant Protein MAF, % In vitro Significance C-TMA and no coexisting conditions (i.e., primary aHUS) M00018 F/3 92 + 12 PEX, Ecu CR, Rec. C3 c.481C>T R161W <0.01 GOF 47 Pathogenic CFI c.392T>G L131R <0.01 LOF 48 Pathogenic M11317 M/65 372 + 44 PEX CR CFHR5 c.1412G>A G471E <0.07 Unknown VUS M00016 M/4 311 + 28 PEX, CS CR FHAA c.CFHR1/3 del p.CFHR1/3 del N/A N/A N/A M01609 M/20 287 + 345 PEX CR C3 c.481C>T R161W <0.01 GOF 47 Pathogenic M03103 F/12 339 + 264 PEX ESKD, Rec. C3 …”

Section: Resultsmentioning

confidence: 99%

“… C3 c.481C>T R161W <0.01 GOF 47 Pathogenic C-TMA and coexisting pregnancy (i.e., pregnancy-associated atypical HUS) M00503 F/32 1388 + 212 PEX, CS ESKD, Rec. C3 c.481C>T R161W <0.01 GOF 47 Pathogenic B46 F/31 557 + 77 PEX, Ecu ESKD CFI c.772G>A A258T 0.01-0.03 LOF 48 Pathogenic C-TMA and coexisting kidney transplantation (i.e., de novo TMA after kidney transplantation) B33 M/24 309 – 252 PEX, Ecu CKD G4/T CFI c.148C>G P50A <0.02 LOF 50 Pathogenic aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; CR, complete renal remission; CS, corticosteroids; Ecu, eculizumab; ESKD, end-stage kidney disease; F, female; FHAA, factor H autoantibody; GOF, gain of function; LOF, loss of function; M, male; MAF, minor allele frequency in the European American population according to the Exome Variant Server and Genome Aggregation Database; MAHA, microangiopathic hemolytic anemia; PEX, plasma therapy; Rec, recurrence; TMA, thrombotic microangiopathy; VUS, variant of uncertain significance. Case numbers beginning with a B are from the Brussels cohort, and case numbers beginning with an M are from the Maastricht cohort.…”

Section: Resultsmentioning

confidence: 99%

Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes

Timmermans

Damoiseaux

Wérion

et al. 2021

Kidney International Reports

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Introduction The syndromes of thrombotic microangiopathy (TMA) are diverse and represent severe endothelial damage caused by various mechanisms. The complement system plays a major role in a subset of patients with TMA, and its recognition is of clinical importance because it guides choice and duration of treatment. Methods We studied a well-defined cohort of patients with TMA and hypothesized that assessment of serum-induced ex vivo C5b9 formation on the endothelium and screening for rare variants in complement genes can better categorize TMA. Results Massive ex vivo C5b9 formation was found in all patients with primary atypical hemolytic uremic syndrome ( n / N = 11/11) and in 59% of patients with TMA and coexisting conditions ( n / N = 30/51). Massive ex vivo C5b9 formation was associated with rare genetic variants (45% [ n / N = 20/44] vs. 0% [ n / N = 0/21] patients with normal ex vivo C5b9 formation; P < 0.001). Massive ex vivo C5b9 formation was associated with favorable renal response to therapeutic complement inhibition in patients with TMA and coexisting conditions (86% [ n / N = 12/14] vs. 31% [ n / N = 5/16] of untreated patients; P < 0.001), indicating complement-mediated TMA rather than secondary disease. Among treated patients, the odds ratio for 1-year kidney survival was 12.0 (95% confidence interval 1.2-115.4). TMA recurrence was linked to rare genetic variants in all cases. Patients with normal ex vivo C5b9 formation had an acute, nonrelapsing form of TMA. Conclusions Ex vivo C5b9 formation and genetic testing appears to categorize TMAs into different groups because it identifies complement as a driving factor of disease, with potential therapeutic and prognostic implications.

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Effect of rare coding variants in the CFI gene on Factor I expression levels

Cited by 42 publications

References 39 publications

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy

Differential and Altered Spatial Distribution of Complement Expression in Age-Related Macular Degeneration

Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes

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