DNA Deletions and DNA Polymorphisms of the Low Density Lipoprotein (LDL) Receptor Gene — Their Use in Diagnosis

  • S. E. Humphries
  • A. Dunning
  • R. Taylor
  • A. Kessling
  • B. Horsthemke
Conference paper
Part of the Verhandlungen der Deutschen Gesellschaft für Innere Medizin book series (VDGINNERE, volume 92)


We have used a cloned cDNA probe for the human LDL receptor gene to look for gross alterations in the LDL receptor gene in patients with Familial Hypercholesterolemia (FH). Among 60 UK patients analysed, we have identified 4 patients where FH appears to be caused by deletion of coding sequences either from the 3′ or from the central part of the gene. Presymptomatic diagnosis based on DNA analysis will thus be possible for these families. Presymptomatic diagnosis in the families of the other patients, relies on the use of indirect methods. The LDL receptor gene cDNA probe detects a common restriction fragment length polymorphism (RFLP) with the enzyme PvuII. The variable PvuII site appears to be within an intervening sequence in the 3’ part of the gene. The rare allele frequency of this polymorphism in both normolipidaemic individuals and patients with heterozygous FH is 0.23. Thirty percent of individuals are heterozygous for the polymorphism and their families are thus potentially informative for early diagnosis of FH based on genetic linkage analysis.


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  1. 1.
    Brown MS, Goldstein JL (1974) Expression of the familial hypercholesterolaemia gene in heterozygotes Mechanism for a dominant disorder in man. Science 185:61–63PubMedCrossRefGoogle Scholar
  2. 2.
    Brown MS, Goldstein JL (1974) Familial hypercholesterolaemia Defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methyglutaryl Coenzyme A reductase activity. Proc Natl Acad Sci USA 71:788–792PubMedCrossRefGoogle Scholar
  3. 3.
    Frederickson DS, Goldstein JL, Brown MS (1978) The familial hyperlipoproteinaemias. In: Stanbury JB, Wyngaarden JB and Frederickson DS (eds) The metabolic basis of inherited disease, McGraw-Hill, New York, pp, 604–655Google Scholar
  4. 4.
    Yamamoto T, Davis LG, 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 39:27–38PubMedCrossRefGoogle Scholar
  5. 5.
    Horsthemke B, Kessling AM, Seed M, Wynn V, Williamson R, Humphries SE (1985) Identification of a deletion in the low density lipoprotein (LDL) receptor gene in a patient with familial hypercholesterolaemia. Human Genetics 71:75–78PubMedCrossRefGoogle Scholar
  6. 6.
    Horsthemke B, Beisiegel U, Dunning A, Williamson R, Humphries S (in preparation) Non-homologous crossing-over between two alu-repetitive DNA sequences in the LDL receptor gene: A possible mechanism for a novel mutation in a patient with familial hypercholesterolaemiaGoogle Scholar
  7. 7.
    Horsthemke B, Dunning A, Humphries S (in preparation) Identification of deletions in the human low-density lipoprotein (LDL) receptorGoogle Scholar
  8. 8.
    Lehrman MA, Schneider WJ, Sudhof TC, Brown MS, Goldstein JL, Russell DW (1985) Mutations in LDL receptor: Alu-Alu recombination deletes Exons encoding transmembrane and cytoplasmic domains. Science 227:140–146PubMedCrossRefGoogle Scholar
  9. 9.
    Lehrman MA, Goldstein JL, Brown MS, Russell DW, Schneider WJ (1985) Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain. Cell 47:735–743CrossRefGoogle Scholar
  10. 10.
    Humphries SE, Kessling AM, Horsthemke B, Donald JA, Seed M, Jowett N, Holm M, Galton DJ, Wynn V, Williamson R (1985) A common DNA polymorphisms of the low density lipoprotein (LDL) receptor gene and its use in diagnosis. Lancet i 1003–1005CrossRefGoogle Scholar
  11. 11.
    Hobbs HH, Lehrman MA, Yamamoto T, Russell DW (1985) Polymorphism and evolution of Alu sequences in the human low density lipoprotein receptor gene. Proc Natl Acad Sci USA 82:7651–7655 -PubMedCrossRefGoogle Scholar
  12. 12.
    Sealey PG, Whittaker PA, Southern EM (1985) Removal of repeated sequences from hybridisation probes. Nucleic Acids Research 13:1905–1922PubMedCrossRefGoogle Scholar
  13. 13.
    Myers RM, Larin Z, Maniatis T (1985) Detection of single base substitutions by ribonuclease cleavage at mismatches in RNA:DNA duplexes. Science 230:1242–1246PubMedCrossRefGoogle Scholar
  14. 14.
    Lipid Research Clinics Program (1984) The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 251:356–374Google Scholar

Copyright information

© J. F. Bergmann Verlag, München 1986

Authors and Affiliations

  • S. E. Humphries
    • 1
  • A. Dunning
    • 1
  • R. Taylor
    • 1
  • A. Kessling
    • 1
  • B. Horsthemke
    • 1
  1. 1.Charing Cross Sunley Research CentreHammersmith LondonUK

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