Al-Maghtheh, May; (1995) Autosomal dominant retinitis pigmentosa: mutation screen rhodopsin and indentification of a new genetic locus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Retinitis pigmentosa (RP) is an inherited group of retinal degenerations that are both clinically and genetically heterogeneous. adRP, the autosomal dominant form of RP, shows further heterogeneity. At the start of this project, adRP was known to result from mutations in two photoreceptor specific genes, namely rhodopsin and peripherin/RDS, and as yet an unidentified gene on chromosome 8. During the course of this thesis, four other loci on chromosomes 7p, 7q, 17p, and 17q were identified by linkage analysis. The aims of this thesis were to identify novel mutations in the rhodopsin gene and to identify new genetic loci implicated in adRP. Identification of new mutations in rhodopsin should further elucidate its structural and functional properties. As part of this thesis, four new mutations were identified in this gene in addition to previously reported ones. These include a 42 bp deletion and 150 bp insertion in exon 5, and two point mutations at codons 40 and 216. In the search for a new adRP locus, linkage analysis was performed in a large adRP family known as ADRP5. After exclusion of candidate genes, a total genome search for the disease gene was undertaken; more than 270 markers were genotyped in the family. The disease phenotype was eventually linked to a 22 cM region defined by markers D19S180 and D19S214 on chromosome 19ql3.4. The new locus was given the symbol RPl1. Linkage analysis in the same family with more markers refined the localization of RP11 to an 8 cM region between D19S180 and AFMb005wh1. To further refine this localization and in order to obtain an estimate of the frequency of RP caused by mutations at this locus, 20 more adRP families were genotyped for markers from the disease interval. Two new families, ADRP29 and RP1907 were found to be linked and haplotype analysis in ADRP29 further reduced the RP11 containing region to 5 cM between D19S180 and AFMc001ybl. Another family not included in this thesis has since been found to be linked to this locus. In a total of 27 families analysed by linkage analysis in this laboratory, four mapped to this locus giving an estimation of the frequency of RP11 as 15%. It therefore suggests that mutations at this locus may be the second most common cause of adRP after rhodopsin. The gene for protein kinase C gamma isoenzyme (PRKCG), a member of a large family of serine/threonine protein kinases (PKC), is known to map in the RP11 interval. In Drosophila a mutation in an eye specific PKC gene was found to cause retinal degeneration and photoreceptor deactivation. Therefore, for these and others reasons, PRKCG was suggested as a candidate for RP11. However, a preliminary mutation screen using primers derived from the cDNA sequence failed to detect any mutation in the 19q linked families. Future work will include characterization of the genomic structure of PRKCG and testing it thoroughly, further refinement of the disease locus if PRKCG is excluded, and establishing a YAC contig across the region as the first step towards positional cloning of this RP gene.

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