Interaction of complement factor h and fibulin3 in age-related macular degeneration.

Abstract

Age-related macular degeneration (AMD) is a major cause of vision loss. It is associated with development of characteristic plaque-like deposits (soft drusen) in Bruch's membrane basal to the retinal pigment epithelium (RPE). A sequence variant (Y402H) in short consensus repeat domain 7 (SCR7) of complement factor H (CFH) is associated with risk for "dry" AMD. We asked whether the eye-targeting of this disease might be related to specific interactions of CFH SCR7 with proteins expressed in the aging human RPE/choroid that could contribute to protein deposition in drusen. Yeast 2-hybrid (Y2H) screens of a retinal pigment epithelium/choroid library derived from aged donors using CFH SCR7 baits detected an interaction with EFEMP1/Fibulin 3 (Fib3), which is the locus for an inherited macular degeneration and also accumulates basal to macular RPE in AMD. The CFH/Fib3 interaction was validated by co-immunoprecipitation of native proteins. Quantitative Y2H and ELISA assays with different recombinant protein constructs both demonstrated higher affinity for Fib3 for the disease-related CFH 402H variant. Immuno-labeling revealed colocalization of CFH and Fib3 in globular deposits within cholesterol-rich domains in soft drusen in two AMD donors homozygous for CFH 402H (H/H). This pattern of labeling was quite distinct from those seen in examples of eyes with Y/Y and H/Y genotypes. The CFH 402H/Fib3 interaction could contribute to the development of pathological aggregates in soft drusen in some patients and as such might provide a target for therapeutic intervention in some forms of AMD.

• Authors: M Keith Wyatt, Jen-Yue Tsai, Sanghamitra Mishra, Maria Campos, Cynthia Jaworski, Robert N Fariss, Steven L Bernstein, Graeme Wistow
• Journal: PloS one (PLoS One) Vol. 8 Issue 6 Pg. e68088 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23840815 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• EFEMP1 protein, human
• Extracellular Matrix Proteins
• Recombinant Proteins
• Complement Factor H

Topics

• Aged
• Cells, Cultured
• Choroid (metabolism, pathology)
• Complement Factor H (metabolism)
• Extracellular Matrix Proteins (metabolism)
• Female
• Humans
• Immunoprecipitation (methods)
• Macular Degeneration (metabolism, pathology)
• Male
• Middle Aged
• Recombinant Proteins (metabolism)
• Retinal Pigment Epithelium (metabolism, pathology)