Mechanism of Genetic and Phenotypic Expression in Hereditary Red Cell Membrane Disorders

(1)日本人群中的红细胞紊乱。我们研究了107个独立家庭206例患者的遗传和表型特征。自1974年我开始在这个领域的研究以来，在我的实验室研究的这些患者的总数达到了1265例，共有742个特征。（二）总结果：(1)遗传性球形细胞增多症365个家族669例（55.2%），(2)遗传性椭圆细胞增多症74个家族146例（12.0%），(3)蛋白4.2缺乏症25个家族41例，(4)遗传性口形细胞增多症66个家族107例，(5)红细胞脂质异常27个家族41例，(6)病因不明186个家族247例，(7)其他，分别进行了广泛的调查。（III）研究了红细胞膜蛋白的4个基因，即3带（EPB3）、蛋白4.2 （ELB42）、β-spectrin （SPTB）和锚蛋白（ANK 1）的DNA甲基化状态。SPTB和ANK 1的5′-CG-3′位点完全未甲基化，而ELB42和EPB3的5′-CG-3′位点重度甲基化。研究了DNA甲基化对正常人群、红细胞膜疾病患者以及红系终末分化过程中基因表达的表观遗传学控制。（四）应用分子电镜观察疾病状态下红细胞膜超微结构异常作为表型的变化。（五）这些成果的一部分作为特邀演讲在日本医学协会大会上发表（2003年4月）。

(I) Red cell membrane disorders in the Japanese population. We investigated genetic and phenotypic characteristics in 206 patients of 107 independent families for the recent 3 years (2002-2005). The total numbers of these patients studied at my laboratory became 1265 cases of 742 traits since 1974 when I started my research at this field.(II) As the total results, (1) hereditary spherocytosis was 669 cases of 365 families (55.2%), (2) hereditary elliptocytosis (HE) 146 cases of 74 families (12.0%), (3) protein 4.2 deficiency 41 cases of 25 families, (4) hereditary stomatocytosis (HSt) 107 cases of 66 families, (5) red cell membrane lipid abnormalities 41 cases of 27 families, (6) cases of unknown etiology 247 cases of 186 families, and (7) others, which are under extensive investigation, respectively.(III) State of DNA methylation was studied regarding the 4 genes of red cell membrane proteins, i.e., band 3 (EPB3), protein 4.2 (ELB42), β-spectrin (SPTB), and ankyrin (ANK 1). The 5'-CG-3' sites of SPTB and ANK 1 were totally unmethylated, and those of ELB42 and EPB3 were heavily methylated. Epigenetic control of gene expression by DNA methylation was investigated in normal subjects and patients with red cell membrane disorders, and during erythroid terminal differentiation.(IV) The abnormalities of ultrastructure of red cell membranes as phenotypes in disease states were investigated by molecular electron microscopy.(V) A part of these results was presented at the General Assembly Meetings of the Japan Medical Association as an invited lecture (April, 2003).