TALMUD, P; TYBJAERGHANSEN, A; BHATNAGAR, D; MBEWU, A; MILLER, JP; DURRINGTON, P; HUMPHRIES, S; (1991) RAPID SCREENING FOR SPECIFIC MUTATIONS IN PATIENTS WITH A CLINICAL-DIAGNOSIS OF FAMILIAL HYPERCHOLESTEROLEMIA. ATHEROSCLEROSIS , 89 (2-3) 137 - 141.
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We describe a rapid screening procedure to identify known DNA sequence changes in individuals diagnosed as having heterozygous familial hypercholesterolaemia (FH). The screening is made possible by combining a rapid DNA extraction protocol and small scale polymerase chain reaction DNA amplification, followed by oligonucleotide melting or restriction enzyme digestion. We have screened for two different mutations; firstly a mutation in the apolipoprotein B (apo B) gene that results in the substitution of glutamine (Gln) for arginine (Arg) at amino acid residue 3500 (apo B3500 mutation). Apo B is the principal component of the protein moiety of low density lipoprotein (LDL) and the mutation reduces the affinity for the LDL receptor (LDL-R). Secondly we have screened for a point mutation in the LDL-R gene itself that creates a new PstI restriction enzyme site. This mutation in the LDL-R gene (LDL-R664 mutation) results in the substitution of leucine (Leu) for proline (Pro) at amino acid 664 and is known to slow processing of the LDL-R precursor to the mature form and to reduce the affinity of the receptor on the cell surface for LDL. In 77 unrelated patients with a clinical diagnosis of FH two out of 77 (2.6%) were positive for the apo B3500 mutation. Three (3.9%) were positive for the LDL-R664 mutation. Thus these two mutations might account for 5-6% of patients in the U.K. with a clinical diagnosis of FH (5000-6000 people). The techniques we have used provide a basis for rapid screening of any patient with hypercholesterolaemia and a family history of premature coronary heart disease (CHD) allowing a more precise diagnosis of individuals with an FH phenotype and the possibility of more mutation-specific therapeutic intervention.
|Title:||RAPID SCREENING FOR SPECIFIC MUTATIONS IN PATIENTS WITH A CLINICAL-DIAGNOSIS OF FAMILIAL HYPERCHOLESTEROLEMIA|
|Keywords:||RAPID SCREENING, FAMILIAL HYPERCHOLESTEROLEMIA, APO B-100, FAMILIAL DEFECTIVE APO B-100, POLYMERASE CHAIN REACTION, SMALL SCALE DNA PREPARATION, LOW-DENSITY LIPOPROTEINS, DEFECTIVE APOLIPOPROTEIN-B-100, POINT MUTATION, BINDING, AMPLIFICATION, RECEPTORS|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science|
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