The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice.

Abstract

Age-related macular degeneration (AMD) is the most common cause of vision loss in developed countries. A defining characteristic of this disorder is the accumulation of material between Bruch's membrane and the retinal pigment epithelium (RPE), first as microscopic basal deposits and later as clinically evident drusen. The pathogenesis of these deposits remains to be defined. Biochemical and genetic studies have suggested that inflammation and complement activation may play roles in AMD. Several lines of evidence also suggest that alterations to the extracellular matrix (ECM) of the RPE and choroid contribute to the development of AMD. The inherited macular degeneration Doyne honeycomb retinal dystrophy/Malattia Leventinese is thought to be caused by an R345W mutation in the EFEMP1 gene (also called fibulin-3). The pathogenicity of this mutation has been questioned because all individuals identified to date with the R345W mutation have shared a common haplotype. We investigated the pathogenicity of this mutation in families with early-onset macular degeneration and by generating Efemp1-R345W knockin mice. Genetic studies show that one of the identified families with the R345W mutation has a novel haplotype. The mutant Efemp1-R345W mice develop deposits of material between Bruch's membrane and the RPE, which resemble basal deposits in patients with AMD. These basal deposits contain Efemp1 and Timp3, an Efemp1 interacting protein. Evidence of complement activation was detected in the RPE and Bruch's membrane of the mutant mice. These results confirm that the R345W mutation in EFEMP1 is pathogenic. Further, they suggest that alterations in the ECM may stimulate complement activation, demonstrating a potential connection between these two etiologic factors in macular degeneration.

• Authors: Li Fu, Donita Garland, Zhenglin Yang, Dhananjay Shukla, Anand Rajendran, Erik Pearson, Edwin M Stone, Kang Zhang, Eric A Pierce
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 16 Issue 20 Pg. 2411-22 (Oct 15 2007) ISSN: 0964-6906 [Print] England
• PMID: 17666404 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Efemp1 protein, mouse
• Extracellular Matrix Proteins
• Tryptophan
• Arginine

Topics

• Adolescent
• Adult
• Aged
• Animals
• Arginine (genetics)
• Child
• DNA Mutational Analysis
• Extracellular Matrix Proteins (genetics, metabolism, physiology)
• Female
• Humans
• Macular Degeneration (genetics, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Middle Aged
• Pedigree
• Point Mutation (physiology)
• Tryptophan (genetics)