Votruba, Marcela; (2000) A clinical and molecular genetic study of dominant optic atrophy mapping to chromosome 3q28-qter / m. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Dominant optic atrophy (DOA) is the commonest form of autosomally-inherited (non-glaucomatous) optic neuropathy. Patients present with bilateral visual loss, temporal optic nerve pallor, centro-caecal scotoma, and a colour vision deficit. A gene for dominant optic atrophy (OPAI) was mapped to within 12 cM on chromosome 3q28-qter in 1994. One hundred and fifty eight affected individuals from 41 families were recruited and blood collected for DNA analysis. The clinical, psychophysical, electrophysiological and neuro-ophthalmic features were investigated in affected individuals from pedigrees showing evidence of linkage to chromosome 3q28-qter. Electrophysiological studies suggest that the abnormalities are confined to the retinal ganglion cell. Psychophysical studies implicate magnocellular and parvocellular ganglion cells of the macula region of the retina. Genetic linkage, haplotype and linkage disequilibrium analysis was carried out. The critical disease interval has been substantially refined to a 1.4cM region between markers D3S3669 and D3S3562. No pedigrees mapped to a second locus on chromosome 18q 12.2-12.3. Haplotype analysis of 38 pedigrees revealed evidence of a founder effect in 36. This allowed for the prediction of the most likely position of the disease gene in the critical disease interval to within ca. 400 kb either side of the marker D3S1523. HRY, a positional and functional candidate gene for DOA, was screened by heteroduplex mutation screening and direct sequencing. No disease-associated abnormalities were found in the coding region of HRY. A physical map spanning the critical disease interval was constructed, comprising YAC and PAC clones. STS content mapping was carried out to confirm clone authenticity and establish overlaps to form a contig. A total of nine STSs, including five microsatellites, were used to allow integration with genetic maps of the region. A preliminary transcript map of the OPAI region was generated, with five ESTs mapping in the critical interval. The expression of these ESTs was studied by PCR of cDNA from a range of tissues. The insert of IMAGE clone EST SHGC374I4 was sequenced. Using the physical mapping data two further candidate genes, DAGK3 and GAP43 were excluded from the critical interval.

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