Abstract
Familial hypercholesterolemia (FH) is caused by defective low density lipoprotein (LDL) receptors and is characterized by hypercholesterolemia and premature coronary heart disease. Two strategies can be used to identify the mutation in the LDL receptor gene underlying FH. One strategy is to search for novel mutations by DNA sequencing with or without prior mutation screening. The other strategy is to screen for known mutations. In this study we employed the latter strategy to screen 75 unrelated, Norwegian FH subjects for 38 known mutations. Three of the 38 mutations were detected in our group of FH subjects. Two subjects had FH-Padova, one had FH-Cincinnati-2 and one had FH-Gujerat. When additional unrelated FH heterozygotes were screened for the three mutations, the gene frequencies were 1.3%, 1.0% and 3.0%, respectively. In addition to identifying known mutations we also detected a novel stop codon in codon 541 (S541X). We conclude that screening for known mutations in the LDL receptor gene should be used as a complementary strategy to screening for novel mutations in order to understand the molecular genetics of FH.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Berkman N, Weir BS, Pressman-Schwartz S, Reshef A, Leitersdorf E (1992) Haplotype analysis at the low density lipoprotein receptor locus: application to the study of familial hypercholesterolemia in Israel. Hum Genet 88:405–410
Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge. Clin Chem 18:499–502
Funke H, Klug J, Frossard P, Coleman R, Assmann G (1986) PstI RFLP close to the LDL receptor gene. Nucleic Acids Res 14:7820
Goldstein JL, Brown MS (1989) Familial hypercholesterolemia. In: Scriver CR, Baudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1215–1250
Hansen PS, Rüdiger N, Tybjærg-Hansen A, Færgeman O, Gregersen N (1991) Detection of the apoB-3500 mutation (glutamine for arginine) by gene amplification and cleavage with Mspl. J Lipid Res 32:1229–1233
Hobbs HH, Esser V, Russell DW (1987) Avail polymorphism in the human LDL receptor gene. Nucleic Acids Res 15:379
Hobbs HH, Brown MS, Goldstein JL (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1:445–466
King-Underwood L, Gudnason V, Humphries S, Seed M, Patel D, Knight B, Soutar A (1991) Identification of the 664 proline to leucine mutation in the low density lipoprotein receptor in four unrelated patients with familial hypercholesterolemia in the UK. Clin Genet 40:17–28
Kotze MJ, Retief AE, Brink PA, Welch HFH (1986) A DNA polymorphism in the human low-density lipoprotein receptor gene. S Afr Med J 70:77–79
Kotze MJ, Langenhoven E, Dietzsch E, Retief AE (1987) A RFLP associated with the low-density lipoprotein receptor gene (LDLR). Nucleic Acids Res 15:376
Leitersdorf E, Hobbs HH (1987) Human LDL receptor gene: two ApaLI RFLPs. Nucleic Acids Res 15:2782
Leitersdorf E, Chakravarti A, Hobbs HH (1989) Polymorphic DNA haplotypes at the LDL receptor locus. Am J Hum Genet 44:409–421
Leitersdorf E, Tobin EJ, Davignon J, Hobbs HH (1990) Common low-density lipoprotein receptor mutations in the French Canadian population. J Clin Invest 85: 1014–1023
Leren TP, Solberg K, R0dningen OK, Ose L, Tonstad S, Berg K (1993 a) Evaluation of running conditions for SSCP analysis: Application of SSCP for detection of point mutations in the LDL receptor gene. PCR Method Appl 3: 159–162
Leren TP, Rødningen OK, Røsby O, Solberg K, Berg K (1993b) Screening for point mutations by semi-automated DNA sequencing using Sequenase and magnetic beads. Biotechniques 14:618–623
Leren TP, Solberg K, Rødningen OK, Røsby O, Tonstad S, Ose L, Berg K (1993c) Screening for point mutations of exon 10 of the LDL receptor gene by analysis of single-strand conformation polymorphisms: detection of a non-sense mutation -FH469→Stop. Hum Genet 92:6–10
Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T (1989 a) Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 86:2766–2770
Orita M, Suzuki Y, Sekiya T, Hayashi K (1989 b) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5:874–879
Rødningen OK, Røsby O, Tonstad S, Ose L, Berg K, Leren TP (1992) A 9.6 kilobase deletion in the low density lipoprotein receptor gene in Norwegian familial hypercholesterolemia heterozygotes. Clin Genet 42:288–295
Rødningen OK, Leren TP, Røsby O, Tonstad S, Ose L, Berg K (1993) Haplotype analysis at the low density lipoprotein receptor locus in normal and familial hypercholesterolemia Norwegian subjects. Clin Genet 44:214–220
Soria LF, Ludwig EH, Clarke HRG, Vega GL, Grundy SM, McCarthy BJ (1989) Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 86:587–591
Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, Russell DW (1984) The human LDL receptor: A cysteine-rich protein with multiple Alu sequences in its mRNA. Cell 39:27–38
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Leren, T.P., Sundvold, H., Rødningen, O.K. et al. Screening for known mutations in the LDL receptor gene causing familial hypercholesterolemia. Hum Genet 95, 671–676 (1995). https://doi.org/10.1007/BF00209485
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00209485