Autosomal dominant hypercholesterolemia due to mutant apolipoprotein B genes

载脂蛋白 B 基因突变导致常染色体显性高胆固醇血症

• 批准号: 03671090
• 负责人: HAMAGUCHI Hideo
• 金额: $ 1.34万
• 依托单位: Basic Medical Sciences, University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03671090/
• 关键词: Hypercholesterolemia; Apolipoprotein B gene; LDL receptor gene; Coronary heart disease; Familial hypercholesterolemia; 常染色体性優性遺伝; 優性遺伝性高コレステロール血症; 早発性虚血性心疾患; 優性遺伝性高コレステロ-ル血症; LDLレセプタ-結合ドメイン

Autosomal dominant hypercholesterolemia is an important risk factor for premature coronary heart disease. This study was done to clarify whether autosomal dominant hypercholesterolemia due to mutant apolipoprotein B genes is relatively common. The genes for LDL receptor and apolipoprotein B were analyzed in 45 pedigrees with hypercholesterolemia. Five different partial deletions, two different frameshift mutations and one complex nucleotide sequence changes were detected in the LDL receptor genes from 11 pedigrees. Seven of the 8 mutant LDL receptor mutant genes were novel ones. In addition, LDL receptor gene RFLP haplotype analysis did not deny the possibility that hypercholesterolemia of another 19 pedigrees is due to mutant LDL receptor genes. Hypercholesterolemia was relatively severe(serum cholesterol levels>300mg/dl)and Achilles tendon xanthomas were frequently observed in most of the above 30 pedigrees. In the other 15 pedigrees, hypercholesterolemia and LDL receptor gene RFLP h … More aplotypes were not co-segregated, suggesting that hypercholesterolemia is due to a mutation of the gene(s) other than the LDL receptor gene. Hypercholesterolemia was moderate (serum cholesterol levels, 250-300mg/dl) and Achilles tendon xanthomas were seldom observed in these 15 pedigrees. A linkage analysis between hypercholesterolemia and the genetic markers within the apolipoprotein B gene was done in the 15 pedigrees. In three of the 15 pedigrees, hypercholesterolemia and the genetic marker was not co-segregated. As to the other 12 pedigrees, the linkage analysis was not infomative. For these 12 pedigrees, DNA sequences in the region of the apolipoprotein B gene that codes for the LDL receptor-binding domain have been analyzed in the probands. Thus far, however, abnormalities in the DNA sequences of the apolipoprotein B gene have not been detected. These data suggest that many of hereditary moderate hypercholesterolemia are not due to the mutant LDL receptor genes, though most of relatively severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas are caused by the mutant LDL receptor genes. Further studies are needed to reveal the prevalence of autosomal dominant hypercholesterolemia due to the mutant apolipoprotein B genes. Less

常染色体显性遗传高胆固醇血症是早发冠心病的重要危险因素。这项研究是为了阐明是否常染色体显性高胆固醇血症由于突变载脂蛋白B基因是相对常见的。对45个高胆固醇血症家系进行了LDL受体和载脂蛋白B基因的检测。在11个家系中检测到5个不同的部分缺失、2个不同的移码突变和1个复杂的核苷酸序列改变。8个LDL受体突变基因中有7个为新基因。此外，LDL受体基因RFLP单倍型分析并没有否定另外19个家系的高胆固醇血症是由于LDL受体基因突变的可能性。高胆固醇血症相对严重（血清胆固醇水平> 300 mg/dl），跟腱黄瘤多见于上述30个家系。在其他15个家系中，高胆固醇血症和LDL受体基因RFLP h ...更多信息 单倍型没有共分离，表明高胆固醇血症是由于LDL受体基因以外的基因突变。高胆固醇血症是中度的（血清胆固醇水平，250- 300毫克/分升）和跟腱黄瘤很少观察到在这15个家系。对15个家系进行了载脂蛋白B基因内遗传标记与高胆固醇血症的连锁分析。在15个家系中的3个中，高胆固醇血症和遗传标记没有共分离。其余12个家系的连锁分析结果不具信息性。对于这12个谱系，已在先证者中分析了编码低密度脂蛋白受体结合域的载脂蛋白B基因区域的DNA序列。然而，迄今为止，尚未检测到载脂蛋白B基因的DNA序列的异常。这些数据表明，许多遗传性中度高胆固醇血症不是由于突变的LDL受体基因，虽然大多数相对严重的遗传性高胆固醇血症与跟腱黄瘤是由突变的LDL受体基因。载脂蛋白B基因突变导致的常染色体显性遗传高胆固醇血症的患病率有待进一步研究。少

项目成果

Hideo Hamaguchi: "Genetic approaches to coronary heart disease and hypertension" SpringerーVerlag, 159 (1991)

Hideo Hamaguchi：“冠心病和高血压的遗传学方法”Springer-Verlag，159（1991）

K.YAMAKAWA et al.: "Family studies of the LDL receptor gene of relativel severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas." Hum.Genet.86. 445-449 (1991)

K.YAMAKAWA 等人：“与跟腱黄色瘤相关的相对严重的遗传性高胆固醇血症的 LDL 受体基因的家族研究。”

H.HAMAGUCHI et al.: "Genetic approach to coronary heart disease andhypertension." Springer-Verlag,159 (1991)

H.HAMAGUCHI 等人：“冠心病和高血压的遗传学方法。”

K.Yamakawa-Kobayashi et al.: "Four new nucleotide sequence polymorphisms in the LDL receptor gene detected by SSCP analysis." Hum.Genet.

K.Yamakawa-Kobayashi 等人：“通过 SSCP 分析检测到 LDL 受体基因中的四种新核苷酸序列多态性。”

H.Hamaguchi et al.:"Analysis of genes associated with hypercholesterolemia in the Japanese population. In:Isolation, migration, and health." Cambridge Univ.Press. 154-166 (1992)

H.Hamaguchi 等人：“日本人群中与高胆固醇血症相关的基因分析。见：隔离、迁移和健康。”