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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3092-3101.)
© 1997 American Heart Association, Inc.

Articles

Comparison of the Genetic Defect with LDL-Receptor Activity in Cultured Cells from Patients With a Clinical Diagnosis of Heterozygous Familial Hypercholesterolemia

Xi-Ming Sun; Dilip D. Patel; Brian L. Knight; Anne K. Soutar; ; with the Familial Hypercholesterolaemia Regression Study Group

From the MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.

Correspondence to Dr Anne K. Soutar, MRC Lipoprotein Team, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. E-mail asoutar{at}rpms.ac.uk

Abstract In this study we have analyzed the genetic defect in 42 patients with a diagnosis of heterozygous familial hypercholesterolemia (FH) by Southern blotting, SSCP, and sequencing of PCR-amplified fragments of genomic DNA or sequencing of RT-PCR products from mRNA in cultured cells. The apoB Arg3500Gln mutation was identified in five patients. A molecular defect in the LDL-receptor gene was confirmed in 23 patients; 16 of these mutations have not been described before. No defect in the coding region, intron:exon junctions or proximal promoter of the LDL-receptor gene or in the region of the apoB gene coding for the LDL-receptor binding domain was found in the remaining 14 patients. LDL-receptor activity and protein content of cultured lymphoblasts from the patients was significantly lower in cells from patients with severe rather than mild LDL-receptor mutations. Cells from four patients with no detectable defect showed reduced LDL receptor activity compared with eight normal cell lines, whereas six others had reduced LDL-receptor activity but LDL-receptor protein content within the normal range. Cells from four patients appeared to have normal LDL-receptor function. Cells from two patients with a defined defect also had LDL-receptor activity within the normal range. The findings demonstrate the problems involved in the genetic diagnosis of FH in patients. .

Key Words: mutation • nucleotide sequencing • familial defective apoB • immunoblotting • LDL-receptor activity

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