Abstract
The aim of this thesis was to identify and characterize genetic defects underlying retinal ciliopathies. Initially, genetic defects were detected by homozygosity mapping using high-density genome-wide single nucleotide polymorphism (SNP) arrays in combination with a positional candidate gene approach. After the advent of next generation sequencing technology, the approach shifted to a combination of homozygosity mapping with targeted next generation sequencing, which, finally, was replaced by exome sequencing.
Chapter 2 summarizes all genes, mutations and modifier alleles associated with non-syndromic retinal ciliopathies, the progress that was made in dissecting the associated retinal disease mechanisms, and an evaluation of gene augmentation approaches to antagonize retinal degeneration.
Chapter 3 describes mutation analysis of IQCB1 in 226 individuals affected by Leber congenital amaurosis (LCA). We identified frameshift and nonsense mutations in 12 individuals diagnosed with LCA.
In Chapter 4, we performed restriction fragment length polymorphism analysis of the BBS1 p.Met390Arg allele in 2,007 individuals affected by autosomal recessive retinitis pigmentosa (RP). We found a significant association between this BBS1 variant and non-syndromic autosomal recessive RP and relatively mild forms of Bardet-Biedl syndrome (BBS).
Chapter 5A presents C8orf37 as a new gene involved in RP and cone-rod dystrophy. In Chapter 5B the interactome of C8orf37 is described and the role of C8orf37 in photoreceptors is proposed.
Finally, Chapter 6 is dedicated to the general discussion.
