Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration.
The common variant in the human complement Factor H gene (CFH), with Tyr402His, is linked to age-related macular degeneration (AMD), a prevalent disorder leading to visual impairment and irreversible blindness in elderly patients. Here we show that the risk variant CFH 402His displays reduced binding to C reactive protein (CRP), heparin and retinal pigment epithelial cells. This reduced binding can cause inefficient complement regulation at the cell surface, particularly when CRP is recruited to injured sites and tissue. In addition, we identify the Factor H-like protein 1 (FHL-1), an alternative splice product of the CFH gene as an additional protein that includes the risk residue 402, and thus confers risk for AMD. FHL-1 is expressed in the eye and the FHL-1 402His risk variant shows similar reduced cell binding and likely reduced complement regulatory functions on the cell surface. CFH and FHL-1 may act in concert in the eye and the reduced surface binding may result in inappropriate local complement control, which in turn can lead to inflammation, disturbance of local physiological homeostasis and progression to cell damage. As a consequence, these processes may lead to AMD pathogenesis.
Skerka
Christine
C
Department of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
Lauer
Nadine
N
Weinberger
Andreas A W A
AA
Keilhauer
Claudia N
CN
Sühnel
Jürgen
J
Smith
Richard
R
Schlötzer-Schrehardt
Ursula
U
Fritsche
Lars
L
Heinen
Stefan
S
Hartmann
Andrea
A
Weber
Bernhard H F
BH
Zipfel
Peter F
PF
D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005260:Female; D006639:Histidine / Q000235:genetics; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018411:Spodoptera / Q000235:genetics; D014443:Tyrosine / Q000235:genetics
C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D020033:Protein Isoforms; D014443:Tyrosine; D006639:Histidine; D017242:Complement Factor H