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Hum Mol Genet. 2017 Nov 1;26(21):4203-4214. doi: 10.1093/hmg/ddx310.

Abnormal creatine transport of mutations in monocarboxylate transporter 12 (MCT12) found in patients with age-related cataract can be partially rescued by exogenous chaperone CD147.

Author information

1
Institute of Medical Molecular Genetics, University Zurich, Zurich, Switzerland.
2
Department of Biology, ETH, Zurich, Switzerland.
3
Jules-Gonin Eye Hospital, University Lausanne, Lausanne, Switzerland.
4
Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Institute for Research in Ophthalmology, Sion, Lausanne, Switzerland.
5
Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland.
6
Institute of Physiology.
7
Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
8
Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, Canada.
9
Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore.
10
Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
11
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
12
Neuroscience Center Zurich (ZNZ), University and ETH Zurich, Zurich, Switzerland.

Abstract

Membrane transporters influence biological functions in the ocular lens. Here, we investigate the monocarboxylate transporter 12 (MCT12), also called creatine transporter 2 (CRT2), which is found in the ocular lens and is involved in cataract. As the age-related form affects about half of the population world-wide, understanding relevant pathomechanisms is a prerequisite for exploring non-invasive treatments. We screened the coding exons of the gene SLC16A12 in 877 patients from five cohorts, including Caucasian and Asian ethnicities. A previously identified risk factor, SNP rs3740030, displayed different frequencies in the Asian cohorts but risk could not be established. In 15 patients 13 very rare heterozygous nucleotide substitutions were identified, of which eight led to non-synonymous and four to synonymous amino acid exchanges and one mapped to the canonical splice site in intron 3. Their impact on creatine transport was tested in Xenopus laevis oocytes and human HEK293T cells. Four variants (p.Ser158Pro, p.Gly205Val, p.Pro395Gln and p.Ser453Arg) displayed severe reduction in both model systems, indicating conserved function. Two of these, p.Gly205Val, and p.Ser453Arg, did not localize to the oocyte membrane, suggesting possible impacts on protein interactions for transporter processing. In support, exogenously supplied excess of MCT12's chaperone CD147 in HEK293T cells led to a partial recovery of the defective uptake activity from p.Gly205Val and also from mutant p.Pro395Gln, which did localize to the membrane. Our findings provide first insight in the molecular requirements of creatine transporter, with particular emphasis on rescuing effects by its chaperone CD147, which can provide useful pharmacological information for substrate delivery.

PMID:
29088427
DOI:
10.1093/hmg/ddx310
[Indexed for MEDLINE]

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