Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency
Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency
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DOI：
10.1093/hmg/8.12.2247
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发表时间：
1999-11-01
影响因子：
3.5
通讯作者：
Tsuji, A
中科院分区：
文献类型：
--
作者：
Koizumi, A;Nozaki, J;Tsuji, A
对日本秋田市 973 名无关白领工人的血清游离肉碱水平进行了测定，其中 14 名参与者的血清游离肉碱水平始终低于第五百分位（女性为 28 μM，男性为 38 μM）。对这 14 名受试者的 OCTN2（有机阳离子转运蛋白）基因进行了测序，其中 22 名受试者的肉碱水平在第一次筛查中低于第五百分位数，但在第二次测量中正常，69 名受试者的肉碱水平在两次单独的测量中均正常。多态性序列定义了频率相等的三种主要单倍型。在 9 名肉碱水平较低的受试者中发现了突变：Trp132X（三名）、Ser467Cys（四名）、Trp283Cys（一名）和 Met179Leu（一名）。HEK 细胞的体外表达研究表明，与正常对照相比，Ser467Cys 和 Trp283Cys（但不是 Met179Leu）显着降低了左旋肉碱的摄取。 Trp132X 和 Ser467Cys 与特定单倍型相关，表明创始人效应。日本秋田县杂合子总体患病率的保守估计为 1.01%，估计原发性全身性肉毒碱缺乏症 (MIM 212140) 的发生率为每 40 000 名新生儿中就有 1 人发生。对原发性肉碱缺乏症患者家属的超声心动图研究表明，与野生型相比，OCTN2 突变杂合子更容易出现迟发性良性心脏肥大（比值比 15.1，95% CI 1.39-164）。从两个家庭的三名已故兄弟姐妹（1.5-8 岁）中分离出的 DNA 测序回顾性证实，所有三名已故受试者的 OCTN2 突变都是纯合的。
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 mu M for females and 38 mu 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.