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Updated: Jan 10, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
HTRA1-AS1, an ARMS2-region long non-coding RNA, is downregulated in retinas of age-related macular degeneration
Ping-Wu Zhang1, Zi-He Wan1, Sheng Liu2
1Department of Ophthalmology, Stem Cell Ocular Regenerative Medicine Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine; Baltimore, MD, 21231, USA.
Purpose:
The human 10q26 locus is a major genetic risk factor for age-related macular degeneration (AMD). Fine mapping by linkage and large-scale genome-wide association studies (GWAS) has narrowed this region to a 30-kb interval encompassing the ARMS2 and HTRA1 genes. However, the causative gene(s), risk variants, and underlying pathogenic mechanisms remain unresolved.
Methods:
Long non-coding RNA (lncRNA) candidates within the ARMS2-HTRA1 region were identified using human postmortem retinal RNA-seq data and public databases (NCBI, Ensembl). Candidate transcripts were validated by RT-PCR and Sanger sequencing. Published single-cell RNA-seq datasets were analysed to define cell type-specific expression, and RNA levels were compared between AMD and non-AMD donor retinas. Additionally, expression changes were assessed in human iPSC-derived retinal pigment epithelium (RPE) cells exposed to cigarette smoke extract (CSE) and paraquat (PQT).
Results:
We identified and validated a lncRNA, HTRA1-AS1, and its transcript variants (ENST00000647969.1) within the ARMS2 locus. HTRA1-AS1 overlaps ARMS2 and is transcribed in the antisense orientation. It is predominantly expressed in rod photoreceptors, Müller glia and Choroid/RPE, and its retinal expression was significantly reduced in AMD compared with controls (43 AMD donors vs. 44 controls, p = 0.007). By contrast, HTRA1 mRNA showed no significant difference (p = 0.121). Furthermore, ENST00000647969.1, HTRA1-AS1 and ARMS2 expression increased dramatically, up to 101-fold, 8-fold and 75-fold, respectively, in induced pluripotent stem cells (iPSC)-derived RPE cells following cigarette smoke extract (CSE)-induced oxidative stress but showed no significant change after paraquat treatment.
Conclusion:
These findings suggest that HTRA1-AS1, a dysregulated lncRNA within the ARMS2 locus, may act as a non-coding element contributing to transcriptional mis-regulation underlying AMD pathogenesis.
