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

(I)日本人群中的红细胞膜疾病。我们调查了近3年（2002-2005年）107个独立家系的206例患者的遗传学和表型特征。自1974年我开始研究这一领域以来，在我的实验室研究的这些患者的总数为1265例742个性状。(II)结果表明：（1）遗传性球形红细胞增多症365个家系669例（2）遗传性椭圆形红细胞增多症（HE）74个家系146例（3）蛋白4.2缺乏症25个家系41例，（4）遗传性口细胞增多症（HSt）66个家系107例，（5）红细胞膜脂质异常27个家系41例，（6）病因不明186个家系247例，（7）其他正在广泛调查中。(III)研究了红细胞膜蛋白的4个基因，即，带3（EPB 3）、蛋白4.2（ELB 42）、β-血影蛋白（SPTB）和锚蛋白（ANK 1）。SPTB和ANK 1的5 '-CG-3'位点完全未甲基化，ELB 42和EPB 3的5 '-CG-3'位点高度甲基化。在正常人和红细胞膜疾病患者以及红细胞终末分化过程中，研究了DNA甲基化对基因表达的表观遗传控制。(IV)用分子电子显微镜观察了红细胞膜超微结构的异常，作为疾病状态下的表型。(V)这些结果的一部分作为特邀演讲在日本医学会大会上发表（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).