Mutations in the organic cation carnitine transporter OCTN2 in primary carnitine deficiency

Primary carnitine deficiency is an autosomal recessive disorder of fatty ac id oxidation caused by defective carnitine transport. This disease presents early in life with hypoketotic hypoglycemia or later in life with skeletal myopathy or cardiomyopathy. The gene for this condition maps to 5q31.2-32 and OCTN2, an organic cation/carnitine transporter, also maps to the same c hromosomal region. Here we test the causative role of OCTN2 in primary carn itine deficiency by searching for mutations in this gene in affected patien ts. Fibroblasts from patients with primary carnitine deficiency lacked medi ated carnitine transport. Transfection of patient's fibroblasts with the OC TN2 cDNA partially restored carnitine transport. Sequencing of the OCTN2 ge ne revealed different mutations in two unrelated patients. The first patien t was homozygous (end both parents heterozygous) for a single base pair sub stitution converting the codon for Arg-282 to a STOP codon (R282X). The sec ond patient was a compound heterozygote for a paternal 1-bp insertion produ cing a STOP codon (Y401X) and a maternal 1-bp deletion that produced a fram eshift creating a subsequent STOP codon (458X). These mutations decreased t he levels of mature OCTN2 mRNA and resulted in nonfunctional transporters, confirming that defects in the organic cation/carnitine transporter OCTN2 a re responsible for primary carnitine deficiency.