De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome

Heinen, Stefan; Sánchez-Corral, Pilar; Jackson, Michael S.; Strain, Lisa; Goodship, Judith A.; Kemp, Elizabeth J.; Skerka, Christine; Jokiranta, T. Sakari; Meyers, Kevin; Wagner, Éric; Robitaille, Pierre; Esparza-Gordillo, Jorge; Córdoba, Santiago Rodrı́guez de; Zipfel, Peter F.; Goodship, Timothy H.J.

doi:10.1002/humu.9408

Cited by 135 publications

(115 citation statements)

References 16 publications

(15 reference statements)

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“…6 This hybrid gene encodes a protein product that is identical to a functionally significant fH mutant (Ser1191Leu/Val1197Ala), which we have shown arises by gene conversion. 7 We have also shown that NAHR in this region leads to deletions incorporating CFHR3/CFHR1 and CFHR1/CFHR4, which are associated with the presence of fH autoantibodies in aHUS. [8][9][10] We routinely use multiplex ligation-dependent probe amplification (MLPA) 11 to screen for genomic disorders in aHUS.…”

Section: Introductionmentioning

confidence: 67%

“…The presence of low copy repeats in this region of chromosome 1 is well recognized to predispose to the development of genomic disorders through both gene conversion events 7 and NAHR. 36 The latter has been shown to result in the deletion of genes encoding the fH-related proteins (CFHR1, CFHR3, and CFHR4) 8,10 and the formation of hybrid genes (CFH/CFHR1).…”

Section: Discussionmentioning

confidence: 99%

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A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

Francis

McNicholas

Awan

et al. 2012

Blood

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Genomic disorders affecting the genes encoding factor H (fH) and the 5 factor H related proteins have been described in association with atypical hemolytic uremic syndrome. These include deletions of CFHR3, CFHR1, and CFHR4 in association with fH autoantibodies and the formation of a hybrid CFH/CFHR1 gene. These occur through nonallelic homologous recombination secondary to the presence of large segmental duplications (macrohomology) in this region. Using multiplex ligation-dependent probe amplification to screen for such genomic disorders, we have identified a large atypical hemolytic uremic syndrome family where a deletion has occurred through microhomologymediated end joining rather than nonallelic homologous recombination. In the 3 affected persons of this family, we have shown that the deletion results in formation of a CFH/CFHR3 gene. We have shown that the protein product of this is a 24 SCR protein that is secreted with normal fluid-phase activity but marked loss of complement regulation at cell surfaces despite increased heparin binding. In this study, we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of fH at the cell surface is critically dependent on the structural integrity of the whole molecule. (Blood. 2012;119(2):591-601)

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Section: Introductionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

Francis

McNicholas

Awan

et al. 2012

Blood

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“…However, uncontrolled activation results in collateral damage to surrounding host tissues. Organ damage from alternative complement dysregulation occurs in several renal diseases including atypical hemolytic uremic syndrome (aHUS) (233)(234)(235)(236)(237)(238)(239) and membranoproliferative glomerulonephritis type II (MPGNII) (240,241). In aHUS, widespread blood clot formation and reactive endothelial cell proliferation in small blood vessels can lead to acute renal failure.…”

Section: Association Of Amd With Other Diseasesmentioning

confidence: 99%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden.Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene-which encodes the major inhibitor of the complement alternative pathway-is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

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“…Recombinant fragments of Factor H (SCRs 1-4, 1-5, 1-6, 8-11, 11-15, 15-18, 15-20, 18-20, and 19-20) and FHL-1 (SCRs 1-7) were expressed in the baculovirus system, as described (26). Recombinant CFHR1 and fragments of CFHR1 (SCRs 1-2, 3-4) were expressed in Pichia pastoris, as described (27). The plasminogen gene (NM_000301) was amplified from human liver cDNA (Invitrogen) by PCR using Phusion High Fidelity DNA Polymerase (Finnzymes, Espoo, Finland) or HotStarTaq DNA Polymerase (Qiagen) with specific primers (Table I) introducing the restriction enzyme sites KpnI and XbaI.…”

Section: Expression and Purification Of Recombinant Proteinsmentioning

confidence: 99%

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

Hallström

Mörgelin

Barthel

et al. 2012

The Journal of Immunology

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The opportunistic human pathogen Pseudomonas aeruginosa causes a wide range of diseases. To cross host innate immune barriers, P. aeruginosa has developed efficient strategies to escape host complement attack. In this study, we identify the 57-kDa dihydrolipoamide dehydrogenase (Lpd) as a surface-exposed protein of P. aeruginosa that binds the four human plasma proteins, Factor H, Factor H-like protein-1 (FHL-1), complement Factor H-related protein 1 (CFHR1), and plasminogen. Factor H contacts Lpd via short consensus repeats 7 and 18–20. Factor H, FHL-1, and plasminogen when bound to Lpd were functionally active. Factor H and FHL-1 displayed complement-regulatory activity, and bound plasminogen, when converted to the active protease plasmin, cleaved the chromogenic substrate S-2251 and the natural substrate fibrinogen. The lpd of P. aeruginosa is a rather conserved gene; a total of 22 synonymous and 3 nonsynonymous mutations was identified in the lpd gene of the 5 laboratory strains and 13 clinical isolates. Lpd is surface exposed and contributes to survival of P. aeruginosa in human serum. Bacterial survival was reduced when Lpd was blocked on the surface prior to challenge with human serum. Similarly, bacterial survival was reduced up to 84% when the bacteria was challenged with complement active serum depleted of Factor H, FHL-1, and CFHR1, demonstrating a protective role of the attached human regulators from complement attack. In summary, Lpd is a novel surface-exposed virulence factor of P. aeruginosa that binds Factor H, FHL-1, CFHR1, and plasminogen, and the Lpd-attached regulators are relevant for innate immune escape and most likely contribute to tissue invasion.

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De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome

Cited by 135 publications

References 16 publications

A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

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