A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negative CFI variants in age-related macular degeneration

Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H ( CFH; FH ) and factor I ( CFI; FI ) are associated with AMD. FH acts as a soluble cofactor t...

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Vydáno v:	Frontiers in immunology Ročník 13; s. 1028760
Hlavní autoři:	Hallam, Thomas M., Cox, Thomas E., Smith-Jackson, Kate, Brocklebank, Vicky, Baral, April J., Tzoumas, Nikolaos, Steel, David H., Wong, Edwin K. S., Shuttleworth, Victoria G., Lotery, Andrew J., Harris, Claire L., Marchbank, Kevin J., Kavanagh, David
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Switzerland Frontiers Media S.A 28.12.2022
Témata:	aHUS (atypical haemolytic uraemic syndrome) AMD (age-related macular degeneration) Complement Complement C3b - genetics Complement Factor H - genetics Complement Factor I - genetics Factor H Factor I Humans Immunology Macular Degeneration - genetics Surface plasmon resonance Factor H AMD (age-related macular degeneration) PNH (paroxysmal nocturnal haemoglobinuria) C3G (C3 Glomerulopathy) Complement Surface plasmon resonance aHUS (atypical haemolytic uraemic syndrome) Factor I
ISSN:	1664-3224, 1664-3224
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Abstract	Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H ( CFH; FH ) and factor I ( CFI; FI ) are associated with AMD. FH acts as a soluble cofactor to facilitate FI’s cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin- CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD.
AbstractList	Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H (CFH; FH) and factor I (CFI; FI) are associated with AMD. FH acts as a soluble cofactor to facilitate FI's cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin-CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD.Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H (CFH; FH) and factor I (CFI; FI) are associated with AMD. FH acts as a soluble cofactor to facilitate FI's cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin-CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD. Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H (CFH; FH) and factor I (CFI; FI) are associated with AMD. FH acts as a soluble cofactor to facilitate FI’s cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin-CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD. Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H ( FH and factor I ( FI are associated with AMD. FH acts as a soluble cofactor to facilitate FI's cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin- expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in and was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD. Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H ( CFH; FH ) and factor I ( CFI; FI ) are associated with AMD. FH acts as a soluble cofactor to facilitate FI’s cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin- CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD.
Author	Steel, David H. Brocklebank, Vicky Baral, April J. Hallam, Thomas M. Wong, Edwin K. S. Cox, Thomas E. Tzoumas, Nikolaos Lotery, Andrew J. Kavanagh, David Shuttleworth, Victoria G. Harris, Claire L. Marchbank, Kevin J. Smith-Jackson, Kate
AuthorAffiliation	2 National Renal Complement Therapeutics Centre, Royal Victoria Infirmary , Newcastle upon Tyne , United Kingdom 1 Translational and Clinical Research Institute, Newcastle University , Newcastle upon Tyne , United Kingdom 6 National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre, Biomedical Research Building , Newcastle upon Tyne , United Kingdom 3 Sunderland Eye Infirmary , Sunderland , United Kingdom 4 Biosciences Institute, Newcastle University, International Centre for Life , Newcastle upon Tyne , United Kingdom 5 Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton , Southampton , United Kingdom
AuthorAffiliation_xml	– name: 3 Sunderland Eye Infirmary , Sunderland , United Kingdom – name: 1 Translational and Clinical Research Institute, Newcastle University , Newcastle upon Tyne , United Kingdom – name: 4 Biosciences Institute, Newcastle University, International Centre for Life , Newcastle upon Tyne , United Kingdom – name: 6 National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre, Biomedical Research Building , Newcastle upon Tyne , United Kingdom – name: 2 National Renal Complement Therapeutics Centre, Royal Victoria Infirmary , Newcastle upon Tyne , United Kingdom – name: 5 Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton , Southampton , United Kingdom
Author_xml	– sequence: 1 givenname: Thomas M. surname: Hallam fullname: Hallam, Thomas M. – sequence: 2 givenname: Thomas E. surname: Cox fullname: Cox, Thomas E. – sequence: 3 givenname: Kate surname: Smith-Jackson fullname: Smith-Jackson, Kate – sequence: 4 givenname: Vicky surname: Brocklebank fullname: Brocklebank, Vicky – sequence: 5 givenname: April J. surname: Baral fullname: Baral, April J. – sequence: 6 givenname: Nikolaos surname: Tzoumas fullname: Tzoumas, Nikolaos – sequence: 7 givenname: David H. surname: Steel fullname: Steel, David H. – sequence: 8 givenname: Edwin K. S. surname: Wong fullname: Wong, Edwin K. S. – sequence: 9 givenname: Victoria G. surname: Shuttleworth fullname: Shuttleworth, Victoria G. – sequence: 10 givenname: Andrew J. surname: Lotery fullname: Lotery, Andrew J. – sequence: 11 givenname: Claire L. surname: Harris fullname: Harris, Claire L. – sequence: 12 givenname: Kevin J. surname: Marchbank fullname: Marchbank, Kevin J. – sequence: 13 givenname: David surname: Kavanagh fullname: Kavanagh, David
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Copyright	Copyright © 2022 Hallam, Cox, Smith-Jackson, Brocklebank, Baral, Tzoumas, Steel, Wong, Shuttleworth, Lotery, Harris, Marchbank and Kavanagh. Copyright © 2022 Hallam, Cox, Smith-Jackson, Brocklebank, Baral, Tzoumas, Steel, Wong, Shuttleworth, Lotery, Harris, Marchbank and Kavanagh 2022 Hallam, Cox, Smith-Jackson, Brocklebank, Baral, Tzoumas, Steel, Wong, Shuttleworth, Lotery, Harris, Marchbank and Kavanagh
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Keywords	Factor H AMD (age-related macular degeneration) PNH (paroxysmal nocturnal haemoglobinuria) C3G (C3 Glomerulopathy) Complement Surface plasmon resonance aHUS (atypical haemolytic uraemic syndrome) Factor I
Language	English
License	Copyright © 2022 Hallam, Cox, Smith-Jackson, Brocklebank, Baral, Tzoumas, Steel, Wong, Shuttleworth, Lotery, Harris, Marchbank and Kavanagh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: József Dobó, Hungarian Academy of Sciences (MTA), Hungary; Ronald Paul Taylor, University of Virginia, United States This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology Edited by: Brian V. Geisbrecht, Kansas State University, United States These authors share first authorship
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doi: 10.1074/jbc.M110.211839
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Snippet	Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of...
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SubjectTerms	aHUS (atypical haemolytic uraemic syndrome) AMD (age-related macular degeneration) Complement Complement C3b - genetics Complement Factor H - genetics Complement Factor I - genetics Factor H Factor I Humans Immunology Macular Degeneration - genetics Surface plasmon resonance
Title	A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negative CFI variants in age-related macular degeneration
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