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.

Détails

ID Serval
serval:BIB_0A4C20417A37
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
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.
Périodique
Human molecular genetics
Auteur(s)
Stäubli A., Capatina N., Fuhrer Y., Munier F.L., Labs S., Schorderet D.F., Tiwari A., Verrey F., Heon E., Cheng C.Y., Wong T.Y., Berger W., Camargo SMR, Kloeckener-Gruissem B.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Statut éditorial
Publié
Date de publication
01/11/2017
Peer-reviewed
Oui
Volume
26
Numéro
21
Pages
4203-4214
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.

Mots-clé
Age Factors, Aged, Aged, 80 and over, Animals, Basigin/administration & dosage, Basigin/pharmacology, Cataract/drug therapy, Cataract/genetics, Cataract/metabolism, Cohort Studies, Genetic Predisposition to Disease, HEK293 Cells, Humans, Lens, Crystalline/metabolism, Male, Membrane Transport Proteins/genetics, Membrane Transport Proteins/metabolism, Middle Aged, Monocarboxylic Acid Transporters/genetics, Monocarboxylic Acid Transporters/metabolism, Risk Factors, Xenopus laevis
Pubmed
Web of science
Open Access
Oui
Création de la notice
08/11/2017 11:20
Dernière modification de la notice
20/08/2019 12:32
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