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X. Shu, S. Clark, A. Dodds, F. Slingsby, A. Day, R. Sim, A. Wright; Biochemical Evidence of Pathogenetic Overlap Between Late Onset Retinal Macular Degeneration and Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):11. doi: https://doi.org/.
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A founder mutation in the C1QTNF5 short-chain collagen gene results in late-onset retinal macular degeneration (L-ORMD), which resembles age-related macular degeneration (AMD). The Y402H and other variants in the complement factor H (CFH) gene increase the risk of AMD. The aim was to investigate a possible interaction between C1QTNF5 and CFH.
Full length C1QTNF5 was expressed in a mammalian expression system, while its gC1q domain was expressed in a bacterial expression system. Both proteins were purified using Ni-NTA super-flow columns. Full length CFH was purified from human plasma. Recombinant segments of CFH, consisting of complement control protein domains 6-8 (CCP6-8), containing either 402Y or 402H alleles, were expressed in bacteria. The interaction between C1QTNF5, CFH and heparin were examined using binding assays and surface plasmon resonance (Biacore).
C1QTNF5 was found to interact in a dose-dependent manner both with purified human CFH and with CCP6-8 CFH modules via the gC1q domain of C1QTNF5. There was a difference between the C1QTNF5 interaction with the 402Y and 402H alleles in the CCP6-8 construct. Preliminary data also showed dose-dependent binding of C1QTNF5 to heparin.
The C1QTNF5 interaction with both CFH and heparin suggests that C1QTNF5 may influence the regulatory activity of CFH, which is important in susceptibility to AMD. These results raise the possibility that there is pathogenetic overlap between L-ORMD and AMD.
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