Exploring the role of non-coding variation in inherited retinal dystrophies: NMNAT1 regulatory mutations as a proof of concept

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.