A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry

Medjeral-Thomas, Nicholas; Malik, Talat H.; Patel, Mitali; Tóth, Tibor; Cook, H. Terence; Tomson, Charles; Pickering, Matthew C.

doi:10.1038/ki.2013.348

Cited by 61 publications

(45 citation statements)

References 10 publications

(16 reference statements)

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“…For example, C5a has a t 1/2 of 3 minutes and the rate of disappearance of C3d is much slower than that of C3c (12,13). The concept that disparate convertase dysregulation is phenotypically important is well supported by a handful of familial cases of C3G segregating specific point mutations or genetic rearrangements (14)(15)(16)(17)(18)(19)(20)(21)(22). These cases provide crucial insight into the phenotypic consequences of variable degrees of convertase dysregulation, whereas biomarker profiling of C3G illustrates the spectrum of complement dysregulation that occurs, highlighting differences in the relative degrees of unchecked activity of the C3 and C5 convertases.…”

Section: Discussionmentioning

confidence: 99%

Defining the Complement Biomarker Profile of C3 Glomerulopathy

Zhang

Nester

Martin

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives C3 glomerulopathy (C3G) applies to a group of renal diseases defined by a specific renal biopsy finding: a dominant pattern of C3 fragment deposition on immunofluorescence. The primary pathogenic mechanism involves abnormal control of the alternative complement pathway, although a full description of the disease spectrum remains to be determined. This study sought to validate and define the association of complement dysregulation with C3G and to determine whether specific complement pathway abnormalities could inform disease definition.Design, setting, participants, & measurements This study included 34 patients with C3G (17 with C3 glomerulonephritis [C3GN] and 17 with dense deposit disease [DDD]) diagnosed between 2008 and 2013 selected from the C3G Registry. Control samples (n=100) were recruited from regional blood drives. Nineteen complement biomarkers were assayed on all samples. Results were compared between C3G disease categories and with normal controls.Results Assessment of the alternative complement pathway showed that compared with controls, patients with C3G had lower levels of serum C3 (P,0.001 for both DDD and C3GN) and factor B (P,0.001 for both DDD and C3GN) as well as higher levels of complement breakdown products including C3d (P,0.001 for both DDD and C3GN) and Bb (P,0.001 for both DDD and C3GN). A comparison of terminal complement pathway proteins showed that although C5 levels were significantly suppressed (P,0.001 for both DDD and C3GN) its breakdown product C5a was significantly higher only in patients with C3GN (P,0.05). Of the other terminal pathway components (C6-C9), the only significant difference was in C7 levels between patients with C3GN and controls (P,0.01). Soluble C5b-9 was elevated in both diseases but only the difference between patients with C3GN and controls reached statistical significance (P,0.001). Levels of C3 nephritic factor activity were qualitatively higher in patients with DDD compared with patients with C3GN.Conclusions Complement biomarkers are significantly abnormal in patients with C3G compared with controls. These data substantiate the link between complement dysregulation and C3G and identify C3G interdisease differences.

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Section: Discussionmentioning

confidence: 99%

Defining the Complement Biomarker Profile of C3 Glomerulopathy

Zhang

Nester

Martin

et al. 2014

Clinical Journal of the American Society of Nephrology

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“…CFHR5 nephropathy is a common cause of renal disease in Cyprus; 45,46 however, a different genetic mutation resulting in the same protein abnormality has been described in a family without Cypriot ancestry. 50 Mutations in other CFHR genes have also been associ ated with C3 glomerulopathies. A mutation that creates a hybrid CFHR3-1 gene leads to a familial form of C3GN that was originally called MPGN type III because it shows frequent intramembranous and subepithelial deposits.…”

Section: Clinico-pathological Correlationmentioning

confidence: 98%

Histopathology of MPGN and C3 glomerulopathies

Cook

Pickering

2014

Nat Rev Nephrol

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'Membranoproliferative' describes glomerular injury characterized by capillary wall thickening and mesangial expansion owing to increased matrix deposition and hypercellularity. The presence of immune deposits is indicative of membranoproliferative glomerulonephritis (MPGN). Historically, MPGN was further classified into three types according to the appearance and site of the electron-dense deposits seen by electron microscopy, but it is now recognized that many cases show only deposition of the complement component C3, owing to abnormal control of the alternative pathway of complement activation-these cases are now classified as C3 glomerulopathies. Not all cases of C3 glomerulopathy, however, show an MPGN pattern. C3 glomerulopathies include dense deposit disease, which shows dense osmiophilic deposits, and C3 glomerulonephritis, which shows isolated deposits. In many cases, the genetic mutations or autoantibodies responsible for C3 deposition have been identified. Some patients in whom complement control is abnormal will accumulate small amounts of immunoglobulin in their glomeruli and so, in everyday practice, the morphological diagnosis of 'glomerulonephritis with dominant C3' is useful for identifying patients who require investigation of the complement pathway. The recognition that many cases of MPGN are C3 glomerulopathies and that the underlying cause can often be identified in immunoglobulin-associated cases means that the diagnosis of idiopathic MPGN is now very uncommon.

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“…C3 glomerulopathies include dense deposit disease (DDD), C3 glomerulonephritis and complement factor H-related Yuste C et al . Pathogenesis of glomerular haematuria (CFHR) genes mutations [54] , such as hybrid CFHR3-1 gene and an internal duplication within the CFHR5 gene [55] . C3 glomerulopathy's incidence has been estimated in 1-2 cases/million people, independently of gender, although it has been reported an increased severity in males.…”

Section: Primary Gbm Disordersmentioning

confidence: 99%

Pathogenesis of glomerular haematuria

Yuste

Gutiérrez

Sevillano

et al. 2015

WJN

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Haematuria was known as a benign hallmark of some glomerular diseases, but over the last decade, new evidences pointed its negative implications on kidney disease progression. Cytotoxic effects of oxidative stress induced by hemoglobin, heme, or iron released from red blood cells may account for the tubular injury observed in human biopsy specimens. However, the precise mechanisms responsible for haematuria remain unclear. The presence of red blood cells (RBCs) with irregular contours and shape in the urine indicates RBCs egression from the glomerular capillary into the urinary space. Therefore glomerular haematuria may be a marker of glomerular filtration barrier dysfunction or damage. In this review we describe some key issues regarding epidemiology and pathogenesis of haematuric diseases as well as their renal morphological findings.

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A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry

Cited by 61 publications

References 10 publications

Defining the Complement Biomarker Profile of C3 Glomerulopathy

Defining the Complement Biomarker Profile of C3 Glomerulopathy

Histopathology of MPGN and C3 glomerulopathies

Pathogenesis of glomerular haematuria

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