Zito, Ilaria; (2001) A molecular genetic study of X-linked retinal diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The X chromosome is home to a large number of genes involved in retinal disease. Two diseases studied in detail in this thesis are X-linked retinitis pigmentosa (XLRP) and X- linked congenital stationary night blindness (CSNBX). XLRP and CSNBX share some clinical features in that patients are initially diagnosed as night blind, however XLRP is a progressive degenerative disease which eventually results in blindness, whilst CSNBX is a milder disease with no disease progression. At the outset of this study four distinct XLRP loci had been described on the short arm of the X-chromosome (RP2, RP3, RP6 and RP15) and the RPGR gene at the RP3 locus had been identified. Linkage data also suggested the presence of at least two CSNBX genes on the short arm of the X chromosome, potentially allelic with XLRP loci. Using haplotype and linkage analysis, the clinical resource available was utilised to establish the level of genetic heterogeneity for these diseases and define the proportion of families mapping to each locus. As disease genes were identified, the mutation spectrum in the patient pool was established for RPGR, RP2 and NYX. Novel mutations were identified for RPGR and RP2 accounting for approximately 30% of disease in the XLRP families studied. In addition, sequence analysis of the RPGR gene provided evidence for a non- pathogenic founder complex allele in the population. Screening for NYX mutations revealed that mutations in this gene are the most common cause of CSNBX, and haplotype analysis around common mutations confirmed a founder mutation in three of the families studied. Further genetic heterogeneity for XLRP has been established by the identification of a new locus in Xp22, RP23, and a positional cloning strategy has been employed towards the identification of the disease gene. Eight genes were physically mapped to Xp22 and these were screened for mutations. A search for new genes, using bioinformatics to detect ESTs, led to the characterisation of several potential transcripts. A family clinically identified as XLRP with additional symptoms, including non- sensorineural deafness, recurrent chest infections and sinus infections, suggested an associated cilia abnormality as the cause of disease. Haplotype analysis revealed disease segregation at the RP3 locus and an RPGR mutation was subsequently identified. This is the first description of such a phenotype and associated genotype and its implications are discussed.

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