Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity.

作者：Clive R. Pullinger, L K Hennessy, Jon E. Chatterton, W Liu, James Love, Carl M. Mendel, Petter Frost, Mary J. Malloy, Verne N. Schumaker, John P. Kane · 发表于：Journal of Clinical Investigation · 年份：1995 · DOI：10.1172/jci117772 · 被引用次数：204 · 研究领域：Lipoproteins and Cardiovascular Health、Protease and Inhibitor Mechanisms、Genomics and Rare Diseases

Detection of new ligand-defective mutations of apolipopro- tein B (apoB) will enable identification of sequences in- volved in binding to the LDL receptor.Genomic DNA from patients attending a lipid clinic was screened by singlestrand conformation polymorphism analysis for novel muta- tions in the putative LDL receptor-binding domain of apoB-100.A 46-yr-old woman of Celtic and Native Ameri- can ancestry with primary hypercholesterolemia (total cho- lesterol [TC] 343 mg/dl; LDL cholesterol [LDL-C] 241 mg/ dl) and pronounced peripheral vascular disease was found to be heterozygous for a novel Arg3531-Cys mutation, caused by a C-T transition at nucleotide 10800.One unrelated 59yr-old man of Italian ancestry was found with the same mutation after screening 1,560 individuals.He had coronary heart disease, a TC of 310 mg/dl, and an LDL-C of 212 mg/ dl.A total of eight individuals were found with the defect in the families of the two patients.They had an age-and sex-adjusted TC of 240±14 mg/dl and LDL-C of 169±+10 mg/dl.This compares with eight unaffected family members with age-and sex-adjusted TC of 185±12 mg/dl and LDL- C of 124±+12 mg/dl.In a dual-label fibroblast binding assay, LDL from the eight subjects with the mutation had an affin- ity for the LDL receptor that was 63% that of control LDL.LDL from eight unaffected family members had an affinity of 91%.By way of comparison, LDL from six patients het- erozygous for the Arg3500-Gln mutation had an affinity of 36%.The percenta...