Inherited retinal diseases (IRD) are a major cause of early-onset blindness worldwide, having an
overall prevalence of 1/3,000. The underlying molecular defects have been found in ~65% of
individuals with IRD, mostly located in protein coding regions. However, there is increasing evidence
that a large proportion of mutations in IRD reside in non-coding regions. Particularly interesting
regions in this context are ultraconserved non-coding elements (UCNEs), located in ultraconserved
genomic regulatory blocks. Here, we will focus on the USH2A gene, which is located in the
ultraconserved ESRRG cluster harboring 72 UCNEs. USH2A mutations represent an important cause
of IRD (retinitis pigmentosa) and of deaf-blindness (Usher syndrome type IIa). Although this is one of
the best studied IRD genes, its regulation is unexplored.
The general aim of this project is to provide insight into the cis-regulation of USH2A in the retina.
Specifically, we will characterize the cis-regulatory landscape of the USH2A region in human retina.
Retinal enhancer activity of USH2A UCNEs will be assessed in cellular models. Genomic profiling of
the entire USH2A gene will be conducted in IRD patients with a single USH2A mutation. The
identification and functional characterization of retinal UCNEs will gain insight into the tissuespecific
regulation of USH2A and to the role of UCNEs in the molecular pathogenesis of IRD when
disrupted. Finally, these regions represent potential targets for new treatments.