ABSTRACT
MCT4 (SLC16A3) is the third member of the monocarboxylate transporter (MCT) family and is involved in the transportation of metabolically important monocarboxylates such as lactate, pyruvate, acetate and ketone bodies. This study aimed to identify genetic variations of the SLC16A3 gene that may be present in the ethnic Chinese (n = 95) and Indian (n = 96) groups of the Singaporean population. The genetic variations in the promoter, coding region and exon-intron junctions of the SLC16A3 gene encoding the MCT4 transporter were screened by DNA sequencing. A total of 46 genetic variants were detected in the SLC16A3 gene, of which 33 are novel. Of these variants, 22 are located in the promoter regions, 2 in the 5' untranslated region (UTR), 10 in the coding exons (5 nonsynonymous and 5 synonymous variations), 6 in 3'UTR and 6 in the intron. Of the 5 nonsynonymous variants, only 44C>T (Ala15Val) was predicted by PolyPhen and SIFT as having a potentially damaging effect on protein function, whereas 55G>A (Gly19Ser), 574G>A (Val192Met) and 916G>A (Gly306Ser) had conflicting results between the SIFT and PolyPhen algorithms. Finally, 641C>T (Ser214Phe) was predicted to be a tolerated variant.
Subject(s)
Asian People/genetics , Monocarboxylic Acid Transporters/genetics , Polymorphism, Single Nucleotide , 5' Untranslated Regions , Algorithms , Carboxylic Acids/metabolism , Chi-Square Distribution , China/ethnology , Computational Biology , Exons , Gene Frequency , Haplotypes , Humans , India/ethnology , Introns , Monocarboxylic Acid Transporters/chemistry , Monocarboxylic Acid Transporters/metabolism , Phenotype , Promoter Regions, Genetic , Protein Conformation , Singapore/epidemiology , Structure-Activity Relationship , SymportersABSTRACT
MCT1(SLC16A1) is the first member of the monocarboxylate transporter (MCT) and its family is involved in the transportation of metabolically important monocarboxylates such as lactate, pyruvate, acetate and ketone bodies. This study identifies genetic variations in SLC16A1 in the ethnic Chinese group of the Singaporean population (n=95). The promoter, coding region and exon-intron junctions of the SLC16A1 gene encoding the MCT1 transporter were screened for genetic variation in the study population by DNA sequencing. Seven genetic variations of SLC16A1, including 4 novel ones, were found: 2 in the promoter region, 2 in the coding exons (both nonsynonymous variations), 2 in the 3' untranslated region (3'UTR) and 1 in the intron. Of the two mutations detected in the promoter region, the -363-855T>C is a novel mutation. The 1282G>A (Val(428)Ile) is a novel SNP and was found as heterozygotic in 4 subjects. The 1470T>A (Asp(490)Glu) was found to be a common polymorphism in this study. Lastly, IVS3-17A>C in intron 3 and 2258 (755)A>G in 3'UTR are novel mutations found to be common polymorphisms in the local Chinese population. To our knowledge, this is the first report of a comprehensive analysis on the MCT1 gene in any population.
Subject(s)
Asian People/genetics , Genetic Variation , Monocarboxylic Acid Transporters/genetics , Symporters/genetics , Ethnicity/genetics , Humans , Polymorphism, Single Nucleotide , SingaporeABSTRACT
It has increasingly been recognized that few molecules move across the cell membrane without the assistance of transporter proteins. Large superfamilies of transporter proteins have been identified in every living cell, including microorganisms and mitochondria. This report reviews the role of transporters in physiology and pharmacology, and identifies where this may have an impact on drug efficacy and toxicity. This new understanding will require a fresh appreciation of pharmacokinetics and drug effects, as the current paradigms are based largely on the assumption that drug molecules have a reasonable unrestricted permeability across membranes. Rather than just focusing on clearance changes and central compartment pharmacokinetics, it will become increasingly necessary to examine the peripheral tissue distribution of drugs to more accurately predict drug efficacy and toxicity.
