A novel ARMS2 splice variant is identified in human retina

Abstract

Age-related macular degeneration (AMD, MIM 603075) is the major cause of irreversible visual impairment in developed countries. AMD damages photoreceptors located in the central region of the retina (the macula), resulting in an impairment of central visual acuity (Jager et al., 2008). A locus at chromosome 10q26 has been consistently linked to the disease and represents one of the two strongest genetic effects discovered (Weeks et al., 2001; Majewski et al., 2003; Weeks et al., 2004; Kenealy et al., 2004; Fisher et al., 2005). However, it has been difficult to identify with certainty the genetic variant at this locus biologically responsible for modulating risk of AMD. Studies have shown that the AMD-associated haplotype includes thesingle nucleotide polymorphisms (SNPs) rs10490924 in gene ARMS2 (Age-related maculopathy susceptibility 2, previously known as hypothetical LOC387715) and rs11200638 in the promoter region of HTRA1 (High-temperature requirement protein A1) (Jakobsdottir et al., 2005; Rivera et al., 2005; Schmidt et al., 2006; Yang et al., 2006; Dewan et al., 2006; Kanda et al., 2007; Fritsche et al., 2008). Unfortunately, the variations in genes ARMS2 and HTRA1 are in such strong linkage disequilibrium (LD) that their effects are indistinguishable using statistical analysis. While studies have suggested a functional effect for each SNP, evidence that the HTRA1 polymorphism is functional and influences gene expression is inconsistent (Yang et al., 2006; Chan et al., 2007; Kanda et al., 2007; Chowers et al., 2008; Tuo et al., 2008; Kanda et al., 2010; Wang et al., 2010; Yang et al., 2010; Friedrich et al., 2011). This inconsistency, combined with the observation that the ARMS2 rs10490924 variant changes the corresponding amino acid sequence of the protein, suggests that ARMS2 is the more likely AMD gene in this region, although this continues to be debated in the literature.