Summary
In the UK, about 5% of patients with familial hypercholesterolaemia have a detectable deletion or rearrangement of part of the LDL-receptor gene. This results in the detection of shorter or abnormal sized fragments of the LDL-receptor gene in a Southern blot hybridization. This can be used to follow the inheritance of the defective gene, and for diagnosis in the families of these individuals. In the families of the rest of the patients, diagnosis may be possible using linked restriction fragment length polymorphisms (RFLPs) detected with the LDL-receptor probe. There are now ten common RFLPs of the LDL-receptor gene, with variable sites in the 3′ half of the gene. Over 80% of patients are heterozygous for at least one of these RFLPs, and therefore potentially informative for DNA diagnosis. For a foetus at risk of homozygous familial hypercholesterolaemia, antenatal diagnosis may also be possible using these methods. However, family studies require samples to be available from affected or unaffected relatives of the patient, and this limits the applicability of the tests. For some mutations, the base pair change causing the defect in the LDL-receptor itself creates or destroys a site for a restriction enzyme. Such ‘mutation-specific’ RFLPs could be used for population screening, but so far have only been reported for the familial hypercholesterolaemia mutation that is common in Lebanon. In the future it may be possible to develop mutation-specific oligonucleotide probes for the diagnosis of familial hypercholesterolaemia. These would be appropriate for population screening or screening patients with hyperlipidaemia. This information may be useful if different mutations require different therapeutic strategies.
Similar content being viewed by others
References
Antonarakis, S. E., Kazazian, H. H. and Orkin, S. H. DNA polymorphism and molecular pathology of the human globin gene clusters.Hum. Genet. 69 (1985) 1–14
Armston, A. E., Iverson, S. A., Burke, J. F. Diagnosis of familial hypercholesterolaemia using DNA probes for the low-density lipoprotein (LDL) receptor gene.Ann. Clin. Biochem. 25 (1988) 142–149
Berg, K., Pedersen, J. C., Borresen, A. I., Heiberg, A. and Solaas, M. H. Close linkage between a common DNA polymorphism of the low-density lipoprotein (LDL) receptor gene and its use in diagnosis.Cytogenet. Cell. Genet. 40 (1985) 581–582
Botstein, D., White, R. L., Skolnick, M. and Davis, R. W. Construction of a genetic linkage map using restriction fragment length polymorphisms.Am. J. Hum. Genet. 32 (1980) 314–331
Brink, P. A., Steyn, L. T., Bester, A. J. and Steyn, K. Linkage disequilibrium between a marker on the low-density lipoprotein receptor and high cholesterol levels.South Afr. Med. J. 70 (1986) 80–82
Brink, P. A., Steyn, L. T., Coetzee, G. A. and Van der Westhuyzen, D. R. Familial Hypercholesterolaemia in South African Afrikaaners:PvuII andStuI DNA polymorphisms in the LDL-receptor gene consistent with a predominating founder gene effect.Hum. Genet. 77 (1987) 32–35
Conner, B. J., Reyes, A. A., Morin, C., Itakura, K., Teplitz, R. L. and Wallace, R. B. Detection of sickle cellβS globin allele by hybridisation with synthetic oligonucleotides.Proc. Natl. Acad. Sci. USA 80 (1983) 278–282
Funke, H., Klug, J., Frossard, P., Coleman, R. and Assmann, G.PstI RFLP close to the LDL receptor gene.Nucl. Acid Res. 14 (1986a) 7820
Funke, H., Rust, S. and Assmann, G. Detection of apolipoprotein E variants by an oligonucleotide “melting” procedure.Clin. Chem. 32 (1986b) 1285–1289
Geisel, J., Weisshaar, B., Oette, K., Mechtel, M. and Doerfler, W. DoubleMspI RFLP in the human LDL-receptor gene.Nucl. Acid. Res. 15 (1987) 3943
Gluek, C. J., Heckmann, F., Schoenfeld, M.,et al. Neonatal familial type II hyperlipoproteinaemia: cord blood cholesterol in 1800 births.Metabolism 20 (1971) 597–608
Hobbs, H. H., Lehrman, M. A., Yamamoto, T. and Russell, D. W. Polymorphism and evolution of Alu sequences in the human low density lipoprotein receptor gene.Proc. Natl. Acad. Sci. USA 82 (1985) 7651–7655
Hobbs, H. H., Esser, V. and Russell, D. W.AvaII polymorphism in the human LDL receptor gene.Nucl. Acid Res. 15 (1987a) 379
Hobbs, H. H., Brown, M. S., Russell, P. W., Davigon, J. and Goldstein, J. L. Deletion in LDL receptor gene occurs in majority of French Canadians with FH.N. Engl. J. Med. 317 (1987b) 734–737
Horsthemke, B., Kessling, A. M., Seed, M., Wynn, V., Williamson, R. and Humphries, S. E. Identification of a deletion in the low density lipoprotein (LDL) receptor gene in a patient with familial hypercholesterolaemia.Hum. Genet. 71 (1985) 75–78
Horsthemke, B., Beisiegel, U., Dunning, A., Williamson, R. and Humphries, S. 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 hypercholesterolaemia.Eur. J. Biochem. 164 (1987a) 77–81
Horsthemke, B., Dunning, A. and Humphries, S. Identification of deletions in the human low-density lipoprotein (LDL) receptor.J. Med. Genet. 24 (1987b) 144–147
Humphries, S. E., Kessling, A. M., Horsthemke, B., Donald, J. A., Seed, M., Jowett, N., Holm, M., Galton, D. J., Wynn, V. and Williamson, R. A common DNA polymorphism of the low density lipoprotein (LDL) receptor gene and its use in diagnosis.Lancet 1 (1985) 1003–1005
Kotze, M. J., Langenhoven, E., Dietzsch, E., and Retief, A. E. An RFLP associated with the low-density lipoprotein receptor gene (LDLR).Nucl. Acid Res. 15 (1987) 37
Kotze, M. J., Retief, A. E., Brink, P. A. and Weich, H. F. H. A DNA polymorphism in the human low-density lipoprotein receptor gene.S. Afr. J. Med. 70 (1986) 77–79
Kwiterovich, P. O., Levy, R. I. and Frederickson, D. S. Diagnosis of familial type-II hyperlipoproteinaemia.Lancet 1 (1973) 118–121
Lehrman, M. A., Schneider, W. J., Sudhof, T. C., Brown, M. S., Goldstein, J. L. and Russell, D. W. Mutations in LDL-receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains.Science 227 (1985a) 140–146
Lehrman, M. A., Goldstein, J. L., Brown, M. S., Russell, D. W. and Schneider, W. J. Internalization-defective LDL-receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.Cell 47 (1985b) 735–743
Lehrmann, M. A., Goldstein, J. L., Russell, D. W. and Brown, M. S. Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolaemia.Cell 48 (1987a) 827–835
Lehrman, M. A., Schneider, W. J., Brown, M. S., Davis, C. G., Elhammer, A., Russell, D. W. and Goldstein, J. L. The Lebanese allele at the low-density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum.J. Biol. Chem. 262 (1987b) 401–410
Leitersdorf, E. and Hobbs, H. H. Human LDL receptor gene: twoApaLI RFLPs.Nucl. Acid Res. 15 (1987) 2782
Leonard, J. V., Whitelaw, A. G. L., Wolff, O. H., Lloyd, J. K. and Slack, J. Diagnosing famiial hypercholesterolaemia in children by measuring serum cholesterol.Br. Med. J. (1977) 1566–1568
Leppert, M. F., Hasstedt, S. J., Holm, T., O'Connell, P., Wu, L., Ash, O., Williams, R. R. and White, R. A DNA probe for the LDL receptor gene is tightly linked to hypercholesterolaemia in a pedigree with early coronary disease.Am. J. Hum. Genet. 39 (1986) 300–306
Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.J. Am. Med. Assoc. 251 (1984) 356–374
Morris, S. W. and Price, W. H. DNA sequence polymorphisms in the apolipoprotein A-I/C-III gene cluster.Lancet 2 (1985) 1127–1128
Old, J. M., Ward, R. H. T., Karagozlu, F., Petrou, M., Modell, B. and Weatherall, D. J. First-trimester fetal diagnosis for haemoglobinopathies: three cases.Lancet 2 (1982) 1413–1416
Steyn, L. T., Pretorius, A., Brink, P. A. and Bester, A. J. RFLP for the human LDL receptor gene (LDLR):BstEII.Nucl. Acid. Res. 15 (1987) 4702
Yamamoto, T., Davis, L. G., Brown, M. S., Schneider, W. J., Casey, M. L., Goldstein, J. L. and Russell, D. W. The human LDL-receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA.Cell 39 (1984) 27–38
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Humphries, S., Taylor, R., Jeenah, M. et al. The use of recombinant DNA techniques for the diagnosis of familial hypercholesterolaemia. J Inherit Metab Dis 11 (Suppl 1), 33–44 (1988). https://doi.org/10.1007/BF01800569
Issue Date:
DOI: https://doi.org/10.1007/BF01800569