Inherited retinal dystrophies (RDs) are a major cause of early-onset blindness worldwide. The
currently known genetic defects account for ~50% of RD cases and are mostly located in the coding
portion of the genome. However, there is accumulating evidence that a large proportion of
mutations reside in non-protein-coding regions, the so-called “unk DNA” Thus far, several deepintronic
mutations have been described in RD. In addition, we identified two adjacent mutations in
the 5’untranslated region (UTR) of the NMNAT1 gene, linking cis-regulatory mutations to congenital
blindness for the first time.
The aim of this study is to unravel and characterize the role of non-coding variation in the molecular
pathogenesis of inherited RD. First, I aim to explore the cis-regulatory landscape of NMNAT1 in
health and disease by the functional characterization of both 5’TR mutations, as well as dissection
of the promoter region of NMNAT1. This study will provide novel insights into NMNAT1 gene
regulation. Second, I aim to explore the role of non-coding variation in RD by searching for
mutations in key cis-regulatory elements in known RD genes. The mutations identified here will be
potential targets for gene-augmentation and antisense oligonucleotides based gene therapy. Finally,
this study can serve as a model for non-coding variation in RD and Mendelian disease in general.