Novel and recurrent LDLR gene mutations in Pakistani hypercholesterolemia patients.

The majority of patients with the autosomal dominant disorder familial hypercholesterolemia (FH) carry novel mutations in the low density lipoprotein receptor (LDLR) that is involved in cholesterol regulation. In different populations the spectrum of mutations identified is quite different and to date there have been only a few reports of the spectrum of mutations in FH patients from Pakistan. In order to identify the causative LDLR variants the gene was sequenced in a Pakistani FH family, while high resolution melting analysis followed by sequencing was performed in a panel of 27 unrelated sporadic hypercholesterolemia patients.

Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9.

Background: We measured plasma PCSK9 concentrations in healthy men with a PCSK9 (proprotein convertase subtilisin/kexin type 9) loss-of-function variant (p.R46L), in statin-treated patients with a clinical diagnosis of familial hypercholesterolemia (FH) and carrying a PCSK9 gain-of-function mutation (p.D374Y), and in statin-treated patients with FH due to different genetic causes.

Mutation scanning by meltMADGE: validations using BRCA1 and LDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population.

We have developed a mutation-scanning approach suitable for whole population screening for unknown mutations. The method, meltMADGE, combines thermal ramp electrophoresis with MADGE to achieve suitable cost efficiency and throughput. The sensitivity was tested in blind trials using 54 amplicons representing the BRCA1 coding region and a panel of 94 unrelated family breast cancer risk consultands previously screened in a clinical diagnostic laboratory.

Mutation detection in patients with familial hypercholesterolaemia using heteroduplex and single strand conformation polymorphism analysis by capillary electrophoresis.

Mutations in the low-density lipoprotein receptor (LDLR) gene give rise to familial hypercholesterolaemia (FH). In this study we have used a 96-well capillary machine (MegaBACE, Amersham) to develop a single strand conformation polymorphism (SSCP) and heteroduplex method for the detection of mutations in the LDLR gene. We have applied this technique to 101 different mutations including single nucleotide polymorphisms in different exons of the LDLR gene.

Serum homocysteine concentrations, gemfibrozil treatment, and progression of coronary atherosclerosis.

The present study aimed to assess the effect of gemfibrozil on serum total homocysteine (tHcy) concentration and to evaluate the influence of tHcy on the angiographically determined progression of coronary atherosclerosis in a randomised, placebo-controlled trial of 395 post-coronary bypass men with low HDL cholesterol levels. The baseline levels of tHcy and those after 16 months of randomised therapy were measured by high-pressure liquid chromatography. Patients were genotyped for the thermolabile variant of N5,N10-methylenetetrahydrofolate reductase (MTHFR) (677C > T substitution).