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Reduced‐function polymorphisms in the high‐affinity carnitine transporter OCTN2 ( SLC22A5 )
Author(s) -
Urban Thomas J,
Brown Chaline,
Castro Richard A.,
Lagpacan Leah L.,
Taylor Travis R.,
Burchard Esteban G.,
Packman Seymour,
Giacomini Kathleen M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb109-b
Subject(s) - carnitine , biology , allele , lymphoblast , polymorphism (computer science) , exon , genetics , microbiology and biotechnology , gene , biochemistry , cell culture
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. We screened for genetic polymorphisms 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. Additionally, 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 (F17L, L144F, and P549S) were polymorphic in at least one ethnic group. When assayed for functional activity by expression in HEK‐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 (F17L, Y449D, V481F, p<0.05). Lymphoblasts from subjects homozygous for the −207G allele showed increased L‐carnitine transport compared to the −207C/C homozygotes (p<0.05), which was explained by increased OCTN2 mRNA in these cells. This study suggests that natural variants of OCTN2 found in healthy populations may contribute to variation in the disposition of carnitine and some clinically used drugs. Data are available at www.PharmGKB.org . Supported by NIH GM61390 and GM36780.