Abstracts (complete list) - Wissenschaft Online

Christine Skerka, Nadine Lauer, Claudia N Keilhauer, Lars Fritsche, Bernhard H.F.
Weber, Peter F. Zipfel
Defective Binding of Factor H (Y402H) and FHL-1 to CRP and
Collagen in Age Related Macular Degeneration
The common Y402H variant in the human complement Factor H (CFH) is linked to agerelated
macular degeneration (AMD), a prevalent disorder leading to visual impairment
and irreversible blindness in elderly patients. At present it is unclear how the variant of
CFH contributes to the occurrence of drusen and the progression to AMD. In order to
define a molecular role of CFH in AMD we purified CFH from plasma of genotyped AMD
patients and control persons which are homozygous HH402, homozygous YY402 and
heterozygous H/Y402. In addition we recombinantly expressed FHL-1, the alternative
splice product of CFH, with the risk H402 and the protective Y402 variant. Functional
tests were performed to compare these CFH and FHL-1 subtypes. The risk variants
402H of both proteins CFH and FHL-1 showed reduced binding to C reactive protein
(CRP). Using extracellular matrix protein array analysis reduced binding of the risk
variants was identified to collagen 1, a major component of drusen. This reduced
binding may cause inefficient complement regulation at the cell surface, particularly
under conditions of inflammation, when CRP is recruited to injured sites and tissue. CFH
and FHL-1 may act in concert and in the eye the reduced surface binding may result in
inappropriate local complement control, which leads to inflammation, disturbance of
local physiological homeostasis and progression to cell damage. As a consequence,
these processes may lead to AMD pathogenesis.