A missense mutation in the OCTN2 gene associated with residual carnitine transport activity

Primary carnitine deficiency is an autosomal recessive disorder of fatty ac id oxidation caused by defective carnitine transport. This disease can pres ent early in life with hypoketotic hypoglycemia and acute metabolic decompe nsation, or later in life with skeletal or cardiac myopathy. Mutations abol ishing the function of OCTN2, an organic cation/carnitine transporter with twelve putative transmembrane spanning domains, were recently demonstrated in patients with early- and late onset (up to seven years of age) presentat ion of this syndrome. Most of the reported mutations are null alleles. Here we evaluate the OCTN2 gene in a male patient who presented at seven years of age with severe dilated cardiomyopathy, Plasma carnitine levels were und etectable and carnitine transport by his fibroblasts was reduced to about 3 % of normal controls. This patient was homozygous for a single base pair ch ange in exon 8 of the OCTN2 gene (1354G>A) converting the codon for Glu 452 to Lys (E452K) in the predicted intracellular loop between transmembrane d omains 10 and 11. Stable expression of the mutant E452K-OCTN2 cDNA in Chine se hamster ovary (CHO) cells caused a partial increase in carnitine transpo rt to 2-4% of the levels measured in the wild type transporter. This reduce d transport activity was associated with normal Km toward carnitine (3.1 +/ - 1.1 mu M), but markedly reduced Vmax, These results indicate that primary carnitine deficiency can be caused by mutations encoding for carnitine tra nsporters with residual activity, and that the E452K affects a domain not i nvolved in carnitine recognition, Hum Mutat 15:238-245, 2000, (C) 2000 Wile y-Liss, Inc.