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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-59480

Castorino, J J; Gallagher-Colombo, S M; Levin, A V; Fitzgerald, P G; Polishook, J; Kloeckener-Gruissem, B; Ostertag, E; Philp, N J (2011). Juvenile cataract-associated mutation of solute carrier SLC16A12 impairs trafficking of the protein to the plasma membrane. Investigative Ophthalmology and Visual Science, 52(9):6774-6784.

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Abstract

PURPOSE:
SLC16A12 encodes an 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. In the present study, in vitro and in vivo experimental models were used to gain insight into how the SLC16A12 (c.643C>T) mutation leads to cataract formation.
METHODS:
MCT12 peptide antibodies were generated and used to examine the expression of MCT12 in the lens using immuno-confocal microscopy. To determine whether loss of Slc16a12 resulted in cataract formation, a Slc16a12 hypomorphic rat generated by transposon insertional mutagenesis was characterized using RT-PCR, slit lamp microscopy and histologic methods. Exogenous expression of MCT12 and MCT12:214Δ, a mimic of the mutant allele, were used to assess protein expression and trafficking.
RESULTS:
MCT12 protein was detected in the lens epithelium and secondary fiber cells at postnatal day 1. In the Slc16a12(TKO) rat, complete loss of MCT12 did not result in any detectable ocular phenotype. Exogenous expression of MCT12-GFP and MCT12:214Δ-GFP revealed that the full-length protein was trafficked to the plasma membrane (PM), whereas the truncated protein was retained in the endoplasmic reticulum (ER). When both MCT12 and MCT12:214Δ were coexpressed, to mimic the heterozygous patient genotype, the truncated protein was retained in the ER whereas full-length MCT12 was trafficked to the PM. Furthermore, MCT12 was identified as another MCT isoform that requires CD147 for trafficking to the cell surface.
CONCLUSIONS:
These data support a model whereby the SLC16A12 (c.643C>T) mutation causes juvenile cataract by a defect in protein trafficking rather than by haploinsufficiency.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Molecular Genetics
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:10 Mar 2012 19:27
Last Modified:02 Dec 2013 20:28
Publisher:Association for Research in Vision and Ophthalmology
ISSN:0146-0404
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:10.1167/iovs.10-6579
PubMed ID:21778275
Citations:Web of Science®. Times Cited: 4
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