High-Temperature Requirement A Serine Peptidase 1 Gene is Transcriptionally Regulated by Insertion/Deletion Nucleotides Located at the 3 Prime End of Age-Related Maculopathy Susceptibility 2 Gene in Patients with Age-Related Macular Degeneration [Gene Regulation]

December 17th, 2014 by Iejima, D., Itabashi, T., Kawamura, Y., Noda, T., Yuasa, S., Fukuda, K., Oka, C., Iwata, T.

Dry age-related macular degeneration (AMD) accounts for over 85% of AMD cases in the United States, while Japanese AMD patients predominantly progress to wet AMD or polypoidal choroidal vasculopathy. Recent genome-wide association studies have revealed a strong association between AMD and an insertion/deletion sequence between the ARMS2 and HTRA1 genes. Transcription regulator activity was localized in mouse retinas using heterozygous HtrA1 knockout mice in which HtrA1 exon 1 was replaced with beta-galactosidase cDNA, thereby resulting in dominant expression of the photoreceptors. The insertion/deletion sequence significantly induced HTRA1 transcription regulator activity in photoreceptor cell lines, but not in retinal pigmented epithelium or other cell types. A deletion construct of the HTRA1 regulatory region indicated that potential transcriptional suppressors and activators surround the insertion/deletion sequence. Ten double-stranded DNA probes for this region were designed, three of which interacted with nuclear extracts from 661W cells in EMSA. Liquid chromatography-mass spectrometry (LC-MS/MS) of these EMSA bands subsequently identified a protein which bound the insertion/deletion sequence, lysine-rich, CEACAM1 co-isolated protein (LYRIC). In addition, induced pluripotent stem cells from wet AMD patients carrying the insertion/deletion sequence showed significant upregulation of the HTRA1 transcript compared with controls. These data suggest that the insertion/deletion sequence alters the suppressor and activator cis-elements of HTRA1 and triggers sustained upregulation of HTRA1. These results are consistent with a transgenic mouse model that ubiquitously overexpresses HtrA1 and exhibits characteristics similar to those of wet AMD patients.
  • Posted in Journal of Biological Chemistry, Publications
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