Human Molecular Genetics, Vol 8, 2247-2254, Copyright © 1999 by Oxford University Press
A Koizumi, J Nozaki, T Ohura, T Kayo, Y Wada, J Nezu, R Ohashi, I Tamai, Y Shoji, G Takada, S Kibira, T Matsuishi and A Tsuji
Serum free-carnitine levels were determined in 973 unrelated white collar
workers in Akita, Japan. Fourteen of these participants consistently had
serum free-carnitine levels below the fifth percentile (28 #M for females
and 38 #M for males). The OCTN2 (organic cation transporter) gene was
sequenced for these 14 subjects, for 22 subjects whose carnitine levels
were below the fifth percentile in the first screening but were normal in
the second measurement and in 69 individuals with normal carnitine levels
for two separate measurements. Polymorphic sequences defined three major
haplotypes with equal frequency. Mutations were identified in nine subjects
with low carnitine levels: Trp132X (three individuals), Ser467Cys (four),
Trp283Cys (one) and Met179Leu (one). In vitro expression studies in HEK
cells indicated that Ser467Cys and Trp283Cys, but not Met179Leu,
significantly reduced L-carnitine uptake relative to the normal control.
Trp132X and Ser467Cys were associated with specific haplotypes, suggesting
a founder effect. A conservative 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 echocardiographic study of the families of patients with
primary carnitine deficiency revealed that the heterozygotes for OCTN2
mutations were predisposed to late onset benign cardiac hypertrophy (odds
ratio 15.1, 95% CI 1.39- 164) compared with the wild-types. Sequencing of
DNA isolated from three deceased siblings (1.5-8 years) in two families
retrospectively confirmed that all three deceased subjects were homozygous
for the OCTN2 mutations.
ARTICLES
Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency
Department of Hygiene, Akita University School of Medicine, Akita 010- 8543, Japan,
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