Publication details for Professor Stewart ClarkShu, Xinhua, Clark, Simon J., Dodds, Alister W., Slingsby, Fern, Day, Anthony J., Sim, Robert B. & Wright, Alan F. (2007). C1QTNF5, which is mutated in late-onset retinal macular degeneration, interacts with complement factor H. Molecular Immunology 44(1-3): 240-240.
- Publication type: Journal Article
- DOI: 10.1016/j.molimm.2006.07.219
- Further publication details on publisher web site
Author(s) from Durham
Age-related macular degeneration (AMD) is the commonest cause of blindness in the western world. An important pathogenic feature of AMD is the accumulation of both focal (drusen) and diffuse extracellular (basal) deposits in the macula between the retinal pigment epithelium (RPE) and underlying Bruch's membrane. AMD is likely to be genetically complex but the pathogenic mechanism is currently unknown. Late-onset retinal macular degeneration (L-ORMD) is an autosomal dominant disorder with striking clinical and pathological similarity to AMD, and has been described as an excellent model for the most severe neovascular form of AMD. L-ORMD is caused by a single founder Ser163Arg mutation in the complement 1q tumour necrosis factor 5 gene (C1QTNF5, previously called CTRP5). C1QTNF5 encodes an N-terminal signal peptide, a short collagen (Gly-X-Y) repeat and a C-terminal globular complement 1q (gC1q) domain. The Arg163 mutation abolishes secretion and results in protein retention within the endoplasmic reticulum and preferential proteasomal degradation.
Complement factor H (CFH) is a key regulator of the complement system. CFH is composed of 20 domains, termed complement control protein domains (CCPs). There is a Tyr/His polymorphism in CCP7 (residue 384 in the mature protein sequence or 402 including the signal sequence), which increases the risk of AMD. CCP7 contains overlapping binding sites for heparin, C-reactive protein (CRP), streptococcal M protein and other bacterial proteins. Both CFH and C1QTNF5 are expressed in RPE cells. C1QTNF5 has been found to interact directly with purified human CFH and with recombinant segments of CFH consisting of CCPs 6-8, containing either His or Tyr at the polymorphic site. Interaction is via the gC1q domains of C1QTNF5. This suggests that C1QTNF5 may influence a regulatory activity of CFH important in susceptibility to age-related macular degeneration.
21st International Complement Workshop Beijing, China, October 22-26, 2006