Hattori H, Nagano M, Iwata F, Homma Y, Egashira T, Okada T
Research Department, R & D Center, BML, Inc., Kawagoe, Saitama, Japan.
Hum Mutat. 1999;14(1):87. doi: 10.1002/(SICI)1098-1004(1999)14:1<87::AID-HUMU14>3.0.CO;2-N.
We used the denaturing gradient gel electrophoresis (DGGE) method to investigate 120 Japanese patients with familial hypercholesterolemia (FH) for mutations in the promoter region and the 18 exons and their flanking intron sequence of the low density lipoprotein (LDL) receptor gene. Fourteen aberrant DGGE patterns were found, and the underlying mutations were characterized by DNA sequencing. Five novel missense mutations (C317S, F382L A410T, L547V, and E693K), two nonsense mutations (W512X and K790X), four frameshift mutation (355del7, 1246ins5, 1687ins1, and 2035ins1), one splicing mutation (1845+2 T-->C), and two inframe mutations (661ins21 and 1115del9/ins6) were identified. Six of these mutations (L547V, E693K, W512X, 355del7, 1687ins1, and 20354ins1) have not been described before in FH. These newly identified mutations cosegregated in their family members with defective LDL receptor activity and hypercholesterolemia, and are thought to be causal for the FH phenotype. These results demonstrate that there is a broad spectrum of mutations in the LDL receptor gene in the Japanese population.
我们采用变性梯度凝胶电泳（DGGE）方法，对120例日本家族性高胆固醇血症（FH）患者的低密度脂蛋白（LDL）受体基因启动子区域、18个外显子及其侧翼内含子序列中的突变进行了研究。发现了14种异常DGGE模式，并通过DNA测序对潜在突变进行了表征。鉴定出5种新的错义突变（C317S、F382L、A410T、L547V和E693K）、2种无义突变（W512X和K790X）、4种移码突变（355del7、1246ins5、1687ins1和2035ins1）、1种剪接突变（1845+2 T→C）和2种框内突变（661ins21和1115del9/ins6）。其中6种突变（L547V、E693K、W512X、355del7、1687ins1和20354ins1）在FH中以前未曾描述过。这些新鉴定的突变在其家族成员中与缺陷性LDL受体活性和高胆固醇血症共分离，被认为是FH表型的病因。这些结果表明，日本人群中LDL受体基因存在广泛的突变谱。
