Rare and common variants in extracellular matrix gene fibrillin 2 (FBN2) are associated with inherited and age-related macular degeneration, respectively

Abstract

Purpose: Macular degenerative diseases are a major cause of mostly incurable central vision loss in humans and pose substantial healthcare burden. Different forms of macular degeneration encompass monogenic early-onset to complex late-onset forms like age-related macular degeneration (AMD), with considerable clinical and genetic heterogeneity. However, both early and late forms share clinical features and identification of causative genes in Mendelian early-onset forms can provide important insights into complex pathobiology of AMD.

Methods: We sequenced all the protein-coding region of the genome (the “exome”) in four members of a two-generation family with an autosomal dominant form of early onset macular degeneration. We screened additional patients for rare variants in patients with early onset maculopathies. We further tested for an association between a functional FBN2 variant rs154001 (p. Val965Ile) and AMD in over 4000 cases and controls.

Results: We identified a novel segregating mutation, p.Glu1144Lys in FBN2, a cysteine-rich glycoprotein, which forms a principal component of the elastin-rich extracellular matrix (ECM). Sequencing analysis identified additional rare variants in early onset maculopathies and AMD patients. Genes of ECM component have been implicated in both early and late macular degenerations and recent genomewide association studies have identified variants in extracellular/collagen matrix pathway genes (TIMP3, COL8A1, COL10A), conferring susceptibility in AMD patients. This prompted us to explore whether common variants in FBN2 are associated with AMD, where we identified a non-synonymous (Val965Ile) SNP, rs154001, that was found to be associated with AMD (p value= 1.03×10-4). Immunofluorescence studies in human and monkey eye localized the FBN2 protein in Bruch’s membrane, choroid and sclera.

Conclusions: We have identified both rare and common variants in FBN2 in patients with macular degeneration. Abundant expression of FBN2 in sclera, choroid and Bruch’s membrane advocates the role of this novel ECM gene FBN2 in macular disease pathogenesis. More significantly, this study establishes an important link between rare and common forms of macular degenerative diseases.

Keywords: 412 age-related macular degeneration • 539 genetics • 494 degenerations/dystrophies