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Heather Thomson, Cheryl Hawkes, Charles Pierce, Andrew Lotery; Genotype phenotype correlations in Fibulin 5 associated macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):337.
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Fibulin 5 is an extracellular matrix protein which promotes adhesion of endothelial cells through interaction of integrins. Missense variations in the gene which encodes Fibulin 5 (FBLN5) have been associated with age-related macular degeneration (AMD) and the characteristic formation of cuticular drusen (1). A patient presented to Southampton Eye Unit with AMD. Due to the presence of distinct small circular drusen the patient was screened for single nucleotide polymorphisms (SNPs) in FBLN5 by single-strand conformation polymorphism. 2 SNPs were identified in exon 4 of FBLN5, one of which was non-synonymous (Gln-124-Pro). The patient was followed for 10 years until death. Whereupon the patient’s eyes were donated for research.
Optical coherence tomography and fundus imaging were carried out to monitor AMD progression. Immunohistochemistry and western blotting were performed for Fibulin 5 (Santa Cruz Biotechnology, Inc.) and Elastin (Elastin Products Company, Inc.), to determine if there were differences in expression between the central and peripheral regions of the RPE/choroid and retina.
Retinal imaging demonstrated soft and cuticular drusen which did not progress significantly over time. As quantified by western blot analysis there was significantly more Fibulin 5 expression in the central versus peripheral RPE/choroid (p=0.019) and also in the RPE/choroid compared to the retina (p=0.034). This is consistent with immunocytochemical staining intensity and with previously published results (2). Elastin expression was reduced in the retina compared to the RPE/choroid however this did not reach significance. An increase in elastin expression was observed in the peripheral RPE/choroid when compared to the macula region. This was in agreement with immunocytochemical staining.
Fibulin 5 has a diverse range of interactions, including integrin binding and elastinogenesis. The Gln-124-Pro missense mutation has been significantly associated with decreased Fibulin 5 secretion, with a possible corresponding reduction in elastinogenesis (3). Disruption of the elastic tissue of Bruch’s membrane observed in this patient may have contributed to the phenotype of discrete sub-RPE deposits observed clinically. 1) Stone EM et al. N Engl J Med. 2004 351(4):346 2) Mullins RF et al. Exp Eye Res. 2007 84(2):378 3) Lotery AJ et al. Hum Mutat. 2006 27(6):568
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