期刊
SURVEY OF OPHTHALMOLOGY
卷 66, 期 2, 页码 378-401出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.survophthal.2020.10.008
关键词
age-related macular degeneration; atypical hemolytic uremic syn-drome; C3 glomerulopathy; complement system; alternative pathway; complement factor H; subretinal inflammation; genetic variants; pharmacogenomics; complement therapeutics
资金
- Macular Society UK
Age-related macular degeneration has been recently associated with abnormal complement activation, indicating it as a disease of general complement dysregulation. Researchers are exploring the molecular impact of related mutations/polymorphisms and identifying various therapeutic avenues for the disease.
Ophthalmologists are long familiar with the eye showing signs of systemic disease, but the association between age-related macular degeneration and abnormal complement activation, common to several renal disorders, has only recently been elucidated. Although complement activation products were identified in drusen almost three decades ago, it was not until the early 21st century that a single-nucleotide polymorphism in the complement factor H gene was identified as a major heritable determinant of age-related macular degeneration, galvanizing global efforts to unravel the pathogenesis of this common disease. Advances in proteomic analyses and familial aggregation studies have revealed distinctive clinical phenotypes segregated by the functional effects of common and rare genetic variants on the mature protein and its splice variant, factor H-like protein 1. The predominance of loss-of-function, N-terminal mutations implicate age-related macular degeneration as a disease of general complement dysregulation, offering several therapeutic avenues for its modulation. Here, we explore the molecular impact of these mutations/polymorphisms on the ability of variant factor H/factor H-like protein 1 to localize to polyanions, pentraxins, proinflammatory triggers, and cell surfaces across ocular and renal tissues and exert its multimodal regulatory functions and their clinical implications. Finally, we critically evaluate key therapeutic and diagnostic efforts in this rapidly evolving field. 2020 Elsevier Inc. All rights reserved.
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