SERPING1 rs2511988 and age-related macular degeneration

Abstract

Using a two-stage case-control protocol, Sarah Ennis and colleagues (Nov 22, p 1828)1 show an association between the SERPING1 gene and age-related macular degeneration. Although this exciting study provides substantive evidence for association with several closely linked intragenic and extragenic variants, it is unclear which biological mechanisms are affected by the population variability in SERPING1 and which variants have a major role in genetic predisposition to this disease.We inspected gene sequences flanking the newly identified variants and found that one of them (rs2511988) was highly likely to have functional consequences. This single-nucleotide substitution is located 20 base pairs upstream of the 3? splice site of exon 7 and is much closer to the SERPING1 coding sequence than the rs2511989 variant initially discovered after completion of their first screen. The rs2511988 variant (A/G) is adjacent to a branch point sequence (TGTTAAG; branch point is underlined), which has been predicted computationally.2Mutations or variants located in the vicinity of this key exon recognition signal have been shown to promote or inhibit splicing efficiency in several human precursor messenger RNAs.3 In yeast, adenine at the same position relative to the branch site is the preferred base4 and facilitates interactions with the branch point binding protein.5 Although human branch point sequences are much more degenerate than those in yeast,[2] and [3] the rs2511988 variant is likely to alter efficiency of intron 6 removal by interfering with assembly of protein-RNA complexes at the 3? splice site and, ultimately, SERPING1 expression level