Investigations of cataract genetics

Familial cataract is a heterogeneous disorder, characterised by opacity of the lens from an early age, often leading to blindness or severe visual disability. Approximately 20% of congenital cataracts are inherited and can occur in isolation or as part of over 200 genetic disorders. Many inherited cataracts also have an age of onset during childhood and as such are not truly congenital, but have similar aetiologies. There have been fourteen genes identified for isolated familial cataract, but many of the molecular causes remain unknown. Forty-five pedigrees with various forms of familial cataract have been collected from south-eastern Australia. This collection includes 40 with autosomal inheritance, four with X-linked inheritance and one with Nance-Horan Syndrome (NHS), an X-linked syndrome involving congenital cataract, dental abnormalities and mental retardation. Linkage studies of the large pedigree with Nance-Horan Syndrome lead to the refinement of the critical region for this disorder to 1.3 Mb through informative recombination events. Coding regions of all six characterised genes in the region were screened for mutations and shown not to be involved. A novel candidate gene was identified in the draft human genome sequence using gene prediction programs, EST information and comparison with other genomes available in public databases, and the genomic structure of the gene was determined experimentally. The gene was subsequently found to be expressed in all human tissues examined, including tissues affected by NHS such as eye and brain. Additional NHS pedigrees were ascertained and mutations of this novel gene were identified by direct sequencing in five of the six NHS pedigrees. All mutations caused severe truncation of the predicted protein and were not identified in controls. Hence, this novel gene, although its function remains unknown, is believed to be causative for Nance-Horan Syndrome. Analysis of known cataract genes and loci by both linkage analysis and mutation detection techniques in pedigrees with autosomal dominant congenital cataract revealed three mutations in previously known cataract genes. These mutations segregate with the cataract phenotype and are thought to be responsible for the cataract observed in these pedigrees. In addition, linkage analysis in one large pedigree has excluded linkage to most known loci, providing evidence for the existence of an additional locus for isolated congenital cataract. In summary, the molecular defect was determined in three large pedigrees with isolated autosomal dominant congenital cataract, and a novel gene was identified and shown to cause Nance-Horan Syndrome.