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Alan Shiels, Thomas M Bennett, Donna S Mackay, Carla J Siegfried; A novel gene for inherited cataract and glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5038.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited cataract is a clinically important and genetically heterogeneous cause of visual impairment that usually presents at an early age with or without systemic and/or other ocular abnormalities. Here we have identified a new locus for autosomal dominant cataract and high-tension glaucoma co-segregating in an extended pedigree.
Following ethical approval and informed consent, linkage analysis was performed with genome-wide markers, and mutation profiling of candidate genes by targeted next-generation and Sanger sequencing. Expression studies were performed by cDNA amplification, and transfection of cultured cells with a recombinant GFP-reporter construct followed by immunoblotting.
Genome-wide linkage analysis mapped the ocular disease locus to the pericentric region of human chromosome 9. Fine mapping and haplotype analysis refined the disease physical interval to ~40 Mb harboring >270 positional candidate genes. Whole exome and custom-interval next-generation sequencing detected a heterozygous A-to-G transition that co-segregated with disease in the pedigree but was not present in the human reference genome databases or in a panel of ethnically matched controls. This novel missense change resided within an alternatively spliced exon of a gene coding for a channel-protein, and was predicted to result in the substitution of isoleucine-to-methionine (Ile>Met) in a known (reference) transcript variant, and in a novel transcript variant expressed in human lens. In both transcript variants, the Ile>Met substitution was predicted in silico to exert damaging effects on protein function. Furthermore, transient expression studies of a GFP-fusion product predicted that the Ile>Met substitution introduced an alternative translation start-site in several other transcript variants; raising the likelihood of deleterious gain-of-function effects.
These studies identify the first mutation in a channel-protein gene not previously associated with inherited ocular disease in humans, and point to an important role for this gene in normal eye development.
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