AMD (age-related macular degeneration) is the major cause of blindness in the western world, associated with the formation of extracellular deposits called drusen in the macula, i.e. the central region of the retina. These drusen contain cellular debris and proteins, including components of the complement system such as the regulator CFH (complement factor H); dysregulation of complement is thought to play a major role in the development of AMD. CFH acts through its capacity to recognize polyanionic structures [e.g. sulfated GAGs (glycosaminoglycans)] found on host tissues, and thereby inactivates any C3b that becomes deposited. Importantly, a common polymorphism in CFH (Y402H) has been strongly associated with an increased risk of AMD. This polymorphism, which causes a tyrosine to histidine coding change, has been shown to alter the binding of CFH to sulfated GAGs, as well as to other ligands including C-reactive protein, necrotic cells and bacterial coat proteins. Of these, the change in the GAG-recognition properties of CFH is likely to be of most significance to AMD. Recent research has revealed that the disease-associated 402H allotype interacts less well (compared with 402Y) with binding sites within the macula (e.g. Bruch's membrane), where the GAGs heparan sulfate and dermatan sulfate play a major role in mediating the interaction with CFH. Reduced binding of the 402H allotype could result in impaired regulation of complement leading to chronic local inflammation that may contribute to the accumulation of drusen and thus the initiation, development and progression of AMD.
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October 2010
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Conference Article|
September 24 2010
Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology
Simon J. Clark;
Simon J. Clark
*Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, U.K.
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Paul N. Bishop;
Paul N. Bishop
†School of Biomedicine, University of Manchester, Oxford Road, Manchester M13 9PT, U.K., and Manchester Academic Health Science Centre, Central Manchester Foundation Trust, Oxford Road, Manchester M13 9WL, U.K.
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Anthony J. Day
Anthony J. Day
1
*Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, U.K.
1To whom correspondence should be addressed (email anthony.day@manchester.ac.uk).
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Biochem Soc Trans (2010) 38 (5): 1342–1348.
Article history
Received:
March 15 2010
Citation
Simon J. Clark, Paul N. Bishop, Anthony J. Day; Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology. Biochem Soc Trans 1 October 2010; 38 (5): 1342–1348. doi: https://doi.org/10.1042/BST0381342
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