Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa

Abstract

Age-related macular degeneration (ARMD) is the leading cause of irreversible visual loss in the Western world, affecting approximately 25 million people worldwide. The pathogenesis is complex and missense mutations in FBLN5 have been reported in association with ARMD. We have investigated the role of fibulin 5 in ARMD by completing the first European study of the gene FBLN5 in ARMD (using 2 European cohorts of 805 ARMD patients and 279 controls) and by determining the functional effects of the missense mutations on fibulin 5 expression. We also correlated the FBLN5 genotype with the ARMD phenotype. We found two novel sequence changes in ARMD patients that were absent in controls and expressed these and the other nine reported FBLN5 mutations associated with ARMD and two associated with the autosomal recessive disease cutis laxa. Fibulin 5 secretion was significantly reduced (P<0.001) for four ARMD (p.G412E, p.G267S, p.I169 T, and p.Q124P) and two cutis laxa (p.S227P, p.C217R) mutations. These results suggest that some missense mutations associated with ARMD lead to decreased fibulin 5 secretion with a possible corresponding reduction in elastinogenesis. This study confirms the previous work identifying an association between FBLN5 mutations and ARMD and for the first time suggests a functional mechanism by which these mutations can lead to ARMD. It further demonstrates that FBLN5 mutations can be associated with different phenotypes of ARMD (not limited to the previously described cuticular drusen type). Such knowledge may ultimately lead to the development of novel therapies for this common disease.

Fibulin-5 distribution in human eyes: Relevance to age-related macular degeneration

“…The primary cause of vision loss in AMD is choroidal neovascularization, which is characterized by abnormal angiogenesis of the choroidal vasculature through Bruch's membrane. This neovascularization is mediated by VEGF, and it is therefore intriguing that some fibulin-5 missense mutations may alter the regulation of VEGF by fibulin-5, either by reduced fibulin-5 secretion (Lotery et al, 2006) or by reduced affinity of fibulin-5 and VEGF, leading to unregulated blood vessel growth.…”

Highly Penetrant Alleles in Age-Related Macular Degeneration

“…Four variants (Gly412Glu, Gly267Ser, Ile169Thr, Gln124Pro) in fibulin-5 that have been associated with AMD dramatically reduce the protein's secretion, and a similar effect was observed for mutations that have been linked to cutis laxa, a rare connective tissue disorder that is characterized by loose, sagging, inelastic skin that can present together with developmental emphysema and major defects in the systemic and pulmonary arteries (Lotery et al 2006;Schneider et al 2010). The Gly412Glu variant causes aggregation of the protein (Jones et al 2010), and the Gly267Ser variant causes extensive misfolding (Schneider et al 2010), which may explain the reduced secretion of these mutant proteins.…”

“…Interestingly, several patients carrying rare variants in the CFH, CFI, and FBLN5 genes have been reported to have cuticular drusen (Stone et al 2004;Lotery et al 2006;Boon et al 2008Boon et al , 2013van de Ven et al 2012a). This clinical subtype of AMD presents at an earlier age than typical AMD, has a strong familial component, and it has been proposed that genetic factors may play a more important role in its development than in the general AMD population (Grassi et al 2007;van de Ven et al 2012b;Boon et al 2013).…”

Fibulin-5 Protein Is Reduced in the Lung of Patients with Spontaneous Pneumothorax Who Are Under 25 Years Old

“…24) Lotery et al revealed that fibulin-5 secretion was significantly reduced for 4 age-related macular degeneration (p.G412E, p.G267S, p.I169 T, and p.Q124P) and 2 cutis laxa (p.S227P, p.C217R) mutations. 25) They showed that some missense mutations lead to decreased fibulin-5 secretion with a possible corresponding reduction in elastinogenesis. To clarify the mechanism of reduction in fibulin-5 protein, we performed sequence analysis of fibulin-5.…”