The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland.

Abstract

A mutation of the LDL receptor gene very common among Finnish patients with heterozygous familial hypercholesterolemia (FH) was identified. This mutation, designated as FHNorth Karelia, deletes seven nucleotides from exon 6 of the LDL receptor gene, causes a translational frameshift, and is predicted to result in a truncated receptor protein. Only minute quantities of mRNA corresponding to the deleted gene were detected. Functional studies using cultured fibroblasts from the patients revealed that the FH-North Karelia gene is associated with a receptor-negative (or binding-defective) phenotype of FH. Carriers of the FH-North Karelia gene showed a typical xanthomatous form of FH, with mean serum total and LDL cholesterol levels of 12 and 10 mmol/liter, respectively. This mutation was found in 69 (34%) out of 201 nonrelated Finnish FH patients and was especially abundant (prevalence 79%) in patients from the eastern Finland. These results, combined with our earlier data on another LDL receptor gene deletion (FH-Helsinki), demonstrate that two "Finnish-type" mutant LDL receptor genes make up about two thirds of FH mutations in this country, reflecting a founder gene effect. This background provides good possibilities to examine whether genetic heterogeneity affects the clinical presentation or responsiveness to therapeutic interventions in FH. (J. Clin. Invest. 1992.

A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia.

“…Genomic DNA samples of 37 heterozygous FH patients were analyzed for the presence of sequence variants in the 5' regulatory region ofthe LDL receptor gene, using direct semiautomated sequencing of PCR fragments. In previous studies, we had failed to detect any major or minor gene rearrangements by either Southern blotting (17) or single-strand conformation analysis (18) in the coding region of the LDL receptor gene in the samples analyzed in this study. PCR primers for sequence analysis were designed to provide information about the region of the LDL receptor gene that contains known DNA motifs for basal expression and negative regulation by sterols (9).…”

“…Oligonucleotide containing the consensus sequence for Spl bind- Fibroblast Cultures. Human fibroblasts were obtained from skin biopsy specimens of the affected sister of the proband and a healthy subject and maintained in culture under conditions previously described (18). Total cytoplasmic RNA was isolated (25) from fibroblasts that had been incubated for 48 hr with medium containing LPDS.…”

“…Total cytoplasmic RNA was isolated (25) from fibroblasts that had been incubated for 48 hr with medium containing LPDS. Northern blot analysis was carried out as described (18). Binding, internalization, and degradation of 125I-labeled LDL (1251-LDL) by fibroblasts were measured as described by Goldstein et al (22).…”

Deletion of exon 15 of the LDL receptor gene is associated with a mild form of familial hypercholesterolemia. FH-Espoo.

“…89 More than 60% (in eastern parts of the country up to 90%) of the heterozygous FH patients in Finland are carriers of one of the two "Finnish-type" LDL receptor gene mutations, FH-Helsinki or FH-North Karelia. 9 The FH-Helsinki mutation is a 9.5-kb deletion eliminating exons 16 through 18 of the LDL receptor gene 8 ; in the FH-North Karelia gene seven nucleotides from exon 6 are deleted. 9 Both of these Finnish-type LDL receptor mutations result in a typical clinical picture of FH, with elevated serum LDL concentration, tendon xanthomatosis, and premature coronary heart disease (CHD).…”

“…9 The FH-Helsinki mutation is a 9.5-kb deletion eliminating exons 16 through 18 of the LDL receptor gene 8 ; in the FH-North Karelia gene seven nucleotides from exon 6 are deleted. 9 Both of these Finnish-type LDL receptor mutations result in a typical clinical picture of FH, with elevated serum LDL concentration, tendon xanthomatosis, and premature coronary heart disease (CHD). 810 There appear to be no differences in serum lipid levels between patients with these two mutation types.…”