Inherited retinal dystrophies (RD) are a major cause of early-onset blindness worldwide, having an

overall prevalence of ~1/3,000. Over 200 disease genes have been identified, accounting for only

~50% of cases. The RD disease genes encode proteins with a broad range of functions, including

general processes such as pre-mRNA splicing. In general it has been estimated that 15% of diseasecausing

mutations affect pre-mRNA splicing. A myriad of cis-acting splicing mutations have been

identified in patients with RD, such as retinitis pigmentosa (RP) and Usher syndrome. Furthermore,

trans-acting mutations in general pre-mRNA splicing factors predominantly cause autosomal

dominant RP (adRP). Interestingly, we and others found non-coding cis-acting mutations of ABCA4 in

Stargardt disease, one of the most frequent autosomal recessive RD. In addition, our group recently

identified SF3B2, encoding a trans-acting splicing factor involved in early spliceosome assembly, as a

novel disease gene for adRP.

Here it is our aim to functionally study the effects of cis-acting splice site mutations of ABCA4 in

vitro and in vivo and to explore antisense oligonucleotide-mediated rescue in patient-derived cells.

Moreover it is our goal to functionally characterize the trans-acting splicing factor SF3B2 in vitro and

in vivo.

Our study will increase our insights into the role of pre-mRNA splicing in the pathogenesis of RD and

has the potential to uncover novel treatments for inherited blindness.