Jensen H K, Holst H, Jensen L G, Jørgensen M M, Andreasen P H, Jensen T G, Andresen B S, Heath F, Hansen P S, Neve S, Kristiansen K, Faergeman O, Kølvraa S, Bolund L, Gregersen N
Center for Medical Molecular Biology, Aarhus University Hospital, Skejby Sygehus, Arhus N, Denmark.
Atherosclerosis. 1997 May;131(1):67-72. doi: 10.1016/s0021-9150(96)06059-5.
In a group of unrelated Danish patients with familial hypercholesterolemia (FH) we recently reported two common low-density lipoprotein (LDL) receptor mutations, W23X and W66G, accounting for 30% of the cases. In this study, we describe another common LDL receptor mutation, a G to C transition at cDNA position 1730 in exon 12, causing a tryptophan to serine substitution in amino acid position 556 (W556S). In the Danish patients, the W556S mutation was present in 12% of 65 possible mutant alleles. The pathogenicity of the W556S mutation, which is located in one of the five conserved motifs Tyr-Trp-Thr-Asp in the epidermal growth factor homology region, was studied in transfected COS-7 cells expressing normal and mutant LDL receptor cDNAs. Results obtained by immunofluorescence flow cytometry and confocal microscopy, as well as by immunoprecipitation, were compatible with complete retention of the mutant protein in the endoplasmic reticulum. The transport-defective W556S mutation and the W23X and W66G mutations seem to account for about 40% of the LDL receptor defects in Danish families with FH.
在一组无亲缘关系的丹麦家族性高胆固醇血症（FH）患者中，我们最近报告了两种常见的低密度脂蛋白（LDL）受体突变，即W23X和W66G，它们占病例的30%。在本研究中，我们描述了另一种常见的LDL受体突变，即外显子12中cDNA位置1730处的G到C转换，导致氨基酸位置556（W556S）处的色氨酸被丝氨酸取代。在丹麦患者中，W556S突变存在于65个可能的突变等位基因中的12%。在表达正常和突变LDL受体cDNA的转染COS-7细胞中研究了位于表皮生长因子同源区域五个保守基序Tyr-Trp-Thr-Asp之一中的W556S突变的致病性。通过免疫荧光流式细胞术和共聚焦显微镜以及免疫沉淀获得的结果与突变蛋白完全保留在内质网中一致。转运缺陷型W556S突变以及W23X和W66G突变似乎占丹麦FH家族中LDL受体缺陷的约40%。
