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Nancy J. Philp, Barbara Kloeckener-Gruissem, Alex V. Levin, Paul G. FitzGerald, John J. Castorino; Juvenile Cataract-associated Mutation Of Solute Carrier Slc16a12 Impairs Trafficking Of The Protein To The Plasma Membrane. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3414.
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SLC16A12 encodes a orphan member of the monocarboxylate transporter family, MCT12. A nonsense mutation in SLC16A12 (c. 643C>T; p.Q215X) causes juvenile cataract with a dominant inheritance pattern. The purpose of these studies was to determine where MCT12 is expressed in the lens and if the p.Q215X mutation is likely to cause cataract formation because of haplo-insufficiency or from a defect in protein folding or trafficking.
MCT12-EGFP and the mutant MCT12:214Δ-EGFP were expressed in HEK-293 cells and the localization of the proteins was assessed using immuno-confocal microscopy. Ocular phenotype of Slc16a12 null rats was characterized using slit lamp, histological and gene expression analysis.
Exogenous expression of MCT12-EGFP and MCT12:215Δ-EGFP revealed that the full length protein was trafficked to the plasma membrane while the truncated protein was retained in the endoplasmic reticulum (ER). Reconstruction of the heterozygous patient genotype in cell culture showed that the truncated mutant form did not interfere with normal trafficking of full-length MCT12. Expression of MCT12:214Δ, but not full-length MCT12, elicited an unfolded protein response (UPR) as demonstrated by an increase in the ER chaperone GRP78. The lenses of Slc16a12-/- rats were clear and there was no evidence of cataract formation as determined by slit-lamp microscopy, histological and scanning electron microscopy analyses.
These data support a model whereby the mutation in SLC16A12 (c. 643C>T; p.Q215X) causes juvenile cataracts because of a defect in protein trafficking rather than haplo-insufficiency or loss of function.
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