Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanesepopulation and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency

Serum free-carnitine levels were determined in 973 unrelated white collar w orkers in Akita, Japan, Fourteen of these participants consistently had ser um free-carnitine levels below the fifth percentile (28 mu M for females an d 38 mu M for males). The OCTN2 (organic cation transporter) gene was seque nced for these 14 subjects, for 22 subjects whose carnitine levels were bel ow the fifth percentile in the first screening but were normal in the secon d measurement and in 69 individuals with normal carnitine levels for two se parate measurements. Polymorphic sequences defined three major haplotypes w ith equal frequency. Mutations were identified in nine subjects with low ca rnitine levels: Trp132X (three individuals), Ser467Cys (four), Trp283Cys (o ne) and Met179Leu (one), In vitro expression studies in HEK cells indicated that Ser467Cys and Trp283Cys, but not Met179Leu, significantly reduced L-c arnitine uptake relative to the normal control. Trp132X and Ser467Cys were associated with specific haplotypes, suggesting a founder effect. A conserv ative estimate of the overall prevalence of heterozygotes was 1.01% in the Akita prefecture, Japan, giving an estimated incidence of primary systemic carnitine deficiency (MIM 212140) as 1 in 40 000 births. An echocardiograph ic study of the families of patients with primary carnitine deficiency reve aled that the heterozygotes for OCTN2 mutations were predisposed to late on set benign cardiac hypertrophy (odds ratio 15.1, 95% CI 1.39-164) compared with the wild-types. Sequencing of DNA isolated from three deceased sibling s (1.5-8 years) in two families retrospectively confirmed that all three de ceased subjects were homozygous for the OCTN2 mutations.