Elucidating the role of the cis-regulatory landscape of ABCA4 in Stargardt disease, the most common inherited retinal disease

Inherited retinal diseases (IRD) are a major cause of early-onset blindness worldwide. The

underlying molecular defects have been found in ~65% of individuals with IRD, mostly coding

mutations. Due to the rapidly expanding whole genome sequencing, the number of non-coding

mutations is emerging. The paradigm of non-coding variation in IRD is strengthened by a subset of

autosomal recessive (AR) monogenic IRD in which only a single mutation can be found in the coding

region of the expected disease-causing gene. One of the most striking examples is AR Stargardt

disease (STGD1), the most frequent IRD, affecting ~1/8.000 persons and caused by biallelic

mutations in ABCA4. In 20-35% of STGD1 however, no or only one coding variant can be identified.

This renders STGD1 an excellent model disease for non-coding variation. The general aim of this

project is to provide insight into the cis-regulation of ABCA4 in the retina, which is still unknown. We

will decipher the cis-regulatory landscape of the ABCA4 region in human retina. Enhancer activity of

identified retinal cis-regulatory elements (CREs) will be assessed by massively parallel reporter

assays in mouse retinal explants. Genomic profiling of the ABCA4 locus will be conducted in IRD

patients with a single coding ABCA4 mutation. Functional characterization of retinal CREs of the

ABCA4 region will contribute to understanding the regulation of ABCA4 and to the role of CREs in

the molecular pathogenesis of STGD1 when disrupted.