A Smoking Gun

It’s a common story – a disease with a prime suspect, but no smoking gun. Knowing that a gene is likely responsible for AMD pathogenesis isn’t enough to show causation of the disease. Hard evidence, like finding the perpetrator at the scene of the crime, is necessary – and researchers at the Sharon Eccles Steele Center for Translational Medicine (SCTM) are on the case. Genes in chromosome 10q26 are associated with AMD, but the prime gene suspects – age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) – have yet to be caught red handed. Do these genes cause the disease through an active mechanism or is something happening to them to affect their normal function? 

Using human eye tissues, the SCTM investigators demonstrated that donors with risk-associated variants had a reduction of HTRA1 in the retinal pigment epithelium (RPE), within the 10q26 locus, which was not the case in the retina or choroid tissues. The scene of the crime was established. This tissue-specific decrease is caused by the presence of an overlapping sequence of ARMS2, which contains a transcription factor binding site that is disrupted by the AMD risk variant rs36212733. Subsequently, HtrA1 protein was found to be reduced at the RPE-Bruch’s membrane – a crucial interface where HtrA1 would normally be responsible for driving clearance of waste and general maintenance. Notably, in a regular chromosome 10q26 locus, HtrA1 actually increases with age. 

The investigators propose that modulating levels of HtrA1 may offer a new therapeutic avenue for AMD; in the meantime, they’re trying to gather more evidence. Translation from association to causation – finding the smoking gun – could be key to understanding and then mitigating RPE-specific and age-dependent drivers of AMD progression, ultimately helping to save the eyesight of those at high genetic risk of developing the disease.