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Jurian Zuercher, John Neidhardt, Istvan Magyar, Stephan Labs, Anthony T. Moore, Felix C. Tanner, Naushin Waseem, Daniel F. Schorderet, Francis L. Munier, Shomi Bhattacharya, Wolfgang Berger, Barbara Kloeckener-Gruissem; Alterations of the 5′Untranslated Region of SLC16A12 Lead to Age-Related Cataract. Invest. Ophthalmol. Vis. Sci. 2010;51(7):3354-3361. doi: https://doi.org/10.1167/iovs.10-5193.
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Knowledge of genetic factors predisposing to age-related cataract is very limited. The aim of this study was to identify DNA sequences that either lead to or predispose for this disease.
The candidate gene SLC16A12, which encodes a solute carrier of the monocarboxylate transporter family, was sequenced in 484 patients with cataract (134 with juvenile cataract, 350 with age-related cataract) and 190 control subjects. Expression studies included luciferase reporter assay and RT-PCR experiments.
One patient with age-related cataract showed a novel heterozygous mutation (c.-17A>G) in the 5′untranslated region (5′UTR). This mutation is in cis with the minor G-allele of the single nucleotide polymorphism (SNP) rs3740030 (c.-42T/G), also within the 5′UTR. Using a luciferase reporter assay system, a construct with the patient's haplotype caused a significant upregulation of luciferase activity. In comparison, the SNP G-allele alone promoted less activity, but that amount was still significantly higher than the amount of the common T-allele. Analysis of SLC16A12 transcripts in surrogate tissue demonstrated striking allele-specific differences causing 5′UTR heterogeneity with respect to sequence and quantity. These differences in gene expression were mirrored in an allele-specific predisposition to age-related cataract, as determined in a Swiss population (odds ratio approximately 2.2; confidence intervals, 1.23–4.3).
The monocarboxylate transporter SLC16A12 may contribute to age-related cataract. Sequences within the 5′UTR modulate translational efficiency with pathogenic consequences.
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