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

Abstract

Detection of new ligand-defective mutations of apolipoprotein B (apoB) will enable identification of sequences involved in binding to the LDL receptor. Genomic DNA from patients attending a lipid clinic was screened by singlestrand conformation polymorphism analysis for novel mutations in the putative LDL receptor-binding domain of apoB-100. A 46-yr-old woman of Celtic and Native American ancestry with primary hypercholesterolemia (total cholesterol [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 59-yr-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 affinity 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 heterozygous for the Arg3500-Gln mutation had an affinity of 36%. The percentage mass ratio of the defective Cys3531 LDL to normal LDL was 59:41, as determined using the mAb MB19 and dynamic laser light scattering. Thus, the defective LDL had accumulated in the plasma of these patients. Using this mass ratio, it was calculated that the defective Cys353, LDL particles bound with 27% of normal affinity.Deduced haplotypes using 10 apoB gene markers showed J. E. Chatterton's present address is

Common ß-adrenergic receptor polymorphisms are not associated with risk of sudden cardiac death in patients with coronary artery disease

“…19 In order to specifically address the risk for SCD and VA rather than CAD, a CAD control group was identified from patients presenting to the UCSF Cardiology Service and consisted of individuals with prior MI and documented CAD by coronary angiography (≥70% stenosis in ≥1 major arteries) or revascularization procedures. From a cohort of over 16,000 patients, potential CAD Controls were matched on a group level to the SCD Cases with respect to age at index MI ± 5 years, sex, ethnicity, degree of CAD as defined by revascularization procedure (coronary artery bypass graft surgery [CABG] > percutaneous transluminal angioplasty [PTCA]/stent), and duration of follow up since index MI.…”

Molecular Characterization of Iranian Patients with Possible Familial Hypercholesterolemia

“…The latter situation usually results in a mild or severe form of hypercholesterolemia together with an increased risk for early onset atherosclerosis [10,11]. In contrast to LDLR, only a small number of functional mutations have been identified in APOB gene such as R3500Q [12], R3500 W [13], and R3531C [14]. There are very limited data regarding LDLR and APOB gene mutations in Iranian population [15,16].…”

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

“…The majority of FDB cases (2 ± 5% of hypercholesterolaemic individuals) are caused by a single mutation, R3500Q. 6 Two rare mutations are also observed, R3531C 7 and R3500W, 8 and 2.4% of Asian hypercholesterolaemic subjects are reported to have the R3500W mutation. 9 Not all cases of monogenic inherited hypercholesterolaemia are accounted for by mutations in LDLR or APOB.…”