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Research ArticleArticle

Functional Genetic Diversity in the High-Affinity Carnitine Transporter OCTN2 (SLC22A5)

Thomas J. Urban, Renata C. Gallagher, Chaline Brown, Richard A. Castro, Leah L. Lagpacan, Claire M. Brett, Travis R. Taylor, Elaine J. Carlson, Thomas E. Ferrin, Esteban G. Burchard, Seymour Packman and Kathleen M. Giacomini
Molecular Pharmacology November 2006, 70 (5) 1602-1611; DOI: https://doi.org/10.1124/mol.106.028126
Thomas J. Urban
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Renata C. Gallagher
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Chaline Brown
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Richard A. Castro
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Leah L. Lagpacan
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Claire M. Brett
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Travis R. Taylor
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Elaine J. Carlson
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Thomas E. Ferrin
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Esteban G. Burchard
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Seymour Packman
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Kathleen M. Giacomini
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Abstract

Systemic carnitine deficiency (SCD) is a rare autosomal recessive disease resulting from defects in the OCTN2 (SLC22A5) gene, which encodes the high-affinity plasma membrane carnitine transporter. Although OCTN2 is fairly well studied in its relationship with SCD, little is known about the carrier frequency of disease-causing alleles of OCTN2, or of more common functional polymorphisms in this gene. To address these issues, we screened for genetic variants in the OCTN2 coding region by direct sequencing of the exons and flanking intronic region of OCTN2 in a large sample (n = 276) of ethnically diverse subjects. In addition, we established lymphoblastoid cell lines from subjects homozygous for either allele of the previously identified promoter region variant, -207G>C. We found eight amino acid sequence variants of OCTN2, of which three (Phe17Leu, Leu144Phe, and Pro549Ser) were polymorphic in at least one ethnic group. When assayed for functional activity by expression in human embryonic kidney 293 cells, using as probes both the endogenous substrate (l-carnitine) and the organic cation tetraethylammonium, three variants showed functional differences from the reference OCTN2 (Phe17Leu, Tyr449Asp, Val481Phe; p < 0.05). Further studies of the Phe17Leu polymorphism showed a reduced Vmax for l-carnitine transport to approximately 50% of the reference OCTN2. Confocal microscopy studies using an OCTN2-GFP fusion protein showed that Phe17Leu had distinct subcellular localization from the reference OCTN2, with diffuse cytoplasmic retention of Phe17Leu, in contrast to reference OCTN2, which localized specifically to the plasma membrane. Lymphoblasts from subjects homozygous for the -207G allele showed increased l-carnitine transport compared with the -207C/C homozygotes (p < 0.05). This study suggests that although loss-of-function mutations in OCTN2 are likely to be rare, common variants of OCTN2 found in healthy populations may contribute to variation in the disposition of carnitine and some clinically used drugs.

Footnotes

  • Dr. Urban is a recipient of a PhRMA Foundation Predoctoral Fellowship in Pharmaceutics. This work was supported by grants from the National Institutes of Health (GM61390 and GM36780).

  • ABBREVIATIONS: SCD, systemic carnitine deficiency; OCTN2, novel organic cation transporter 2; TEA, tetraethylammonium; SNP, single-nucleotide polymorphism; GFP, green fluorescent protein; HBSS, Hanks' buffered salt solution; LCL, lymphoblastoid cell line.

    • Received June 19, 2006.
    • Accepted August 24, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (5)
Molecular Pharmacology
Vol. 70, Issue 5
1 Nov 2006
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Research ArticleArticle

Functional Genetic Diversity in the High-Affinity Carnitine Transporter OCTN2 (SLC22A5)

Thomas J. Urban, Renata C. Gallagher, Chaline Brown, Richard A. Castro, Leah L. Lagpacan, Claire M. Brett, Travis R. Taylor, Elaine J. Carlson, Thomas E. Ferrin, Esteban G. Burchard, Seymour Packman and Kathleen M. Giacomini
Molecular Pharmacology November 1, 2006, 70 (5) 1602-1611; DOI: https://doi.org/10.1124/mol.106.028126

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Research ArticleArticle

Functional Genetic Diversity in the High-Affinity Carnitine Transporter OCTN2 (SLC22A5)

Thomas J. Urban, Renata C. Gallagher, Chaline Brown, Richard A. Castro, Leah L. Lagpacan, Claire M. Brett, Travis R. Taylor, Elaine J. Carlson, Thomas E. Ferrin, Esteban G. Burchard, Seymour Packman and Kathleen M. Giacomini
Molecular Pharmacology November 1, 2006, 70 (5) 1602-1611; DOI: https://doi.org/10.1124/mol.106.028126
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