Disease relevance of SLC22A5

• Primary carnitine deficiency (OCTN2) gene database  
• We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G-->C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease [1].
• Analysis of chromosome 5q31-32 and psoriasis: confirmation of a susceptibility locus but no association with SNPs within SLC22A4 and SLC22A5 [2].
• Review of all OCTN2 deficiency cases reported so far revealed that this is the first presentation of histopathology in classic familial sudden infant death syndrome (SIDS) with an established SLC22A5 mutation [3].
• Prevalence of SLC22A4 1672T and SLC22A5 -207C Combination Defined TC Haplotype in Hungarian Ulcerative Colitis Patients [4].
• The SCD is an autosomal recessive disorder of fatty acid oxidation characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia and hyperammonemia [5].

High impact information on SLC22A5

• These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease [1].
• Our observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner prompted us to search for mutations in the gene encoding OCTN2, SLC22A5 [6].
• Primary systemic carnitine deficiency (SCD; OMIM 212140) is an autosomal recessive disorder characterized by progressive cardiomyopathy, skeletal myopathy, hypoglycaemia and hyperammonaemia [6].
• Membrane-physiological studies have suggested a defect of the carnitine transport system in the plasma membrane in SCD patients and in the mouse model, juvenile visceral steatosis [6].
• SCD has also been linked to sudden infant death syndrome [6].

Chemical compound and disease context of SLC22A5

• Polymorphisms in the carnitine transporters, encoded by the SLC22A4 and SLC22A5 genes, have been involved in susceptibility to two other autoimmune diseases, rheumatoid arthritis and Crohn's disease [7].
• In this study, the characteristics of L-carnitine transport into hepatocytes were studied by use of cultured human hepatoma HLF cells, which expressed OCTN2 mRNA to a greater extent than OCTN1 mRNA [8].
• Neither H nor SCD appeared to offer protection for the other groups of trauma patients, but surveillance with ultrasound examinations allowed for prompt recognition and treatment of occult deep vein thrombosis [9].
• Erythropoietin is being used more widely in the management of sickle cell disease (SCD, inclusive of homozygous sickle beta, SS, and compound heterozygous sickle beta thalassemia, Sbeta0 thal), often in conjunction with hydroxyurea (HU) [10].

Biological context of SLC22A5

• There was no significant interaction between the SLC22A4/SLC22A5 diplotype and the three CD-associated CARD15 SNPs [11].
• Little correlation was seen with regard to clinical phenotype and the SLC22A4/SLC22A5 diplotype [11].
• Two variants, 1672C>T in SLC22A4 and -207G>C in SLC22A5, were shown to alter these genes' functions and were identified as genetic susceptibility factors for Crohn's disease (CD) [12].
• RESULTS: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D', >0.959) [13].
• Finally, double transfection of OCTN2 with PDZK1 stimulated the uptake by OCTN2 of its endogenous substrate carnitine, and this increase could be accounted for by the 6-fold increase in transport capacity [14].

Anatomical context of SLC22A5

• The interaction of PDZK1 with the C terminus of OCTN2 was also confirmed in a pull-down study using kidney brush-border membrane vesicles [14].
• Northern blot analysis showed that OCTN2 is strongly expressed in kidney, skeletal muscle, heart, and placenta in adult humans [15].
• The OCTN2-specific transcript, 3.5 kb in size, is expressed widely in human tissues and in cell lines of human origin [16].
• We have cloned OCTN2, a new member of the organic cation transporter family, from a human placental trophoblast cell line [16].
• When expressed heterologously in HeLa cells, OCTN2 mediates the transport of tetraethylammonium, a prototypical organic cation, in a pH-dependent manner [16].

Associations of SLC22A5 with chemical compounds

• PDZK1 directly regulates the function of organic cation/carnitine transporter OCTN2 [14].
• When OCTN2 was expressed in HEK293 cells, uptake of L-[3H]carnitine was strongly enhanced in a sodium-dependent manner with Km value of 4.34 microM, whereas typical substrates for previously known organic cation transporters, tetraethylammonium and guanidine, were not good substitutes [15].
• OCTN2-mediated L-[3H]carnitine transport was inhibited by the D-isomer, acetyl-D,L-carnitine, and gamma-butyrobetaine with high affinity and by glycinebetaine with lower affinity, whereas choline, beta-hydroxybutyric acid, gamma-aminobutyric acid, lysine, and taurine were not inhibitory [15].
• The hMATE1 and hMATE2-K, but not hOCTN1 and OCTN2, mediated the cellular accumulation of cisplatin and oxaliplatin without a marked release of lactate dehydrogenase [17].
• Several organic cations, including the neurotoxins 1-methyl-4-phenylpyridinium, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and methamphetamine, compete for the OCTN2-mediated transport process [16].

Physical interactions of SLC22A5

• Coexpression of PDZK2 did not affect carnitine transport activity of OCTN2 with deletion of the last four amino acids, which were found to be important for the interaction, suggesting involvement of physical interaction of the two proteins in the increase of cell surface expression of OCTN2 [18].

Other interactions of SLC22A5

• The expression of Pgp, BCRP, OCTN2 and MCT1 differed along the small intestine, but the expression differences were greater than five-fold only for Pgp [19].
• Between the ileum and colon, seven transcripts were differentially expressed, and MCT1, OCTN2 and MRP3 were expressed at higher levels in the colon than in the small intestine [19].
• Association analysis of SLC22A4, SLC22A5 and DLG5 in Japanese patients with Crohn disease [20].
• In two non-consanguineous Hungarian Roma (Gypsy) children who presented with cardiomyopathy and decreased plasma carnitine levels, we identified homozygous deletion of 17081C of the SLC22A5 gene that results in a frameshift at R282D and leads ultimately to a premature stop codon (V295X) in the OCTN2 carnitine transporter [3].
• Reduction in CRAT, CPT 2, and OCTN2 was more than 85% [21].

Analytical, diagnostic and therapeutic context of SLC22A5

• Evidence for the association of the SLC22A4 and SLC22A5 genes with type 1 diabetes: a case control study [7].
• Site-directed mutagenesis and introduction of residues nonconserved between OCTN1 and OCTN2 in the OCTN2 cDNA indicated that the R341A, L409W, L424Y, and T429I substitutions significantly decreased carnitine transport [22].
• The characteristics of the juvenile visceral steatosis (jvs) mouse, an animal model of SCD showing similar symptoms as humans having this genetic disorder, are also described [5].
• Confocal microscopy of OCTN2 transporters tagged with green fluorescent protein indicated that the Y447C mutant transporters failed to reach the plasma membrane, whereas Y447F, Y449D, and Y449F had normal membrane localization [23].
• Immunoelectron microscopy visualized both OCTN2 and PDZK1 in microvilli of absorptive epithelial cells [24].

References