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. 1990 May;27(5):298–302. doi: 10.1136/jmg.27.5.298

An exon 4 mutation identified in the majority of South African familial hypercholesterolaemics.

M J Kotze 1, L Warnich 1, E Langenhoven 1, L du Plessis 1, A E Retief 1
PMCID: PMC1017079  PMID: 2352257

Abstract

The prevalence of familial hypercholesterolaemia (FH) is significantly higher in the Afrikaans speaking population (Afrikaners) of South Africa than reported in most other populations. A founder gene effect has been proposed to explain the high FH frequency, implying that the same low density lipoprotein (LDL) receptor gene defect is present in the majority of affected Afrikaners. By using DNA amplification and sequence determination, we have detected a point mutation in DNA from two Afrikaner FH homozygotes. A cytosine to guanine base substitution at nucleotide position 681 of the LDL receptor cDNA results in an amino acid change from aspartic acid to glutamic acid at residue 206 in the cysteine rich ligand binding domain of the LDL receptor. Since three previously mapped transport deficient alleles of the LDL receptor were also traced to cysteine rich repeats of the protein, these results suggest that the mutation is responsible for the receptor defective mutation predominantly found in Afrikaner FH homozygotes. The mutation gives rise to an additional DdeI restriction site in DNA of affected subjects and segregation of the mutation with the disease was confirmed in five large Afrikaner FH families. We predict that 65% of affected South African Afrikaners carry this particular base substitution. Amplification of genomic DNA, using the polymerase chain reaction method, and restriction enzyme analysis now permit accurate diagnosis of the mutation in subjects with FH.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Esser V., Russell D. W. Transport-deficient mutations in the low density lipoprotein receptor. Alterations in the cysteine-rich and cysteine-poor regions of the protein block intracellular transport. J Biol Chem. 1988 Sep 15;263(26):13276–13281. [PubMed] [Google Scholar]
  2. Goldstein J. L., Brown M. S. Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasma cholesterol. J Lipid Res. 1984 Dec 15;25(13):1450–1461. [PubMed] [Google Scholar]
  3. Jooste P. L., Benadé A. J., Rossouw J. E. Prevalence of familial hypercholesterolaemia in three rural South African communities. S Afr Med J. 1986 Apr 26;69(9):548–551. [PubMed] [Google Scholar]
  4. Kotze M. J., Langenhoven E., Dietzsch E., Retief A. E. A RFLP associated with the low-density lipoprotein receptor gene (LDLR). Nucleic Acids Res. 1987 Jan 12;15(1):376–376. doi: 10.1093/nar/15.1.376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Kotze M. J., Langenhoven E., Retief A. E., Seftel H. C., Henderson H. E., Weich H. F. Haplotypes identified by 10 DNA restriction fragment length polymorphisms at the human low density lipoprotein receptor gene locus. J Med Genet. 1989 Apr;26(4):255–259. doi: 10.1136/jmg.26.4.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kotze M. J., Langenhoven E., Retief A. E., Steyn K., Marais M. P., Grobbelaar J. J., Oosthuizen C. J., Weich H. F., Benadé A. J. Haplotype associations of three DNA polymorphisms at the human low density lipoprotein receptor gene locus in familial hypercholesterolaemia. J Med Genet. 1987 Dec;24(12):750–755. doi: 10.1136/jmg.24.12.750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kotze M. J., Langenhoven E., Warnich L., Marx M. P., Retief A. E. Molecular characterisation of a low-frequency mutation in exon 8 of the human low-density lipoprotein receptor gene. S Afr Med J. 1989 Oct 21;76(8):402–405. [PubMed] [Google Scholar]
  8. Kotze M. J., Langenhoven E., Warnich L., du Plessis L., Marx M. P., Oosthuizen C. J., Retief A. E. The identification of two low-density lipoprotein receptor gene mutations in South African familial hypercholesterolaemia. S Afr Med J. 1989 Oct 21;76(8):399–401. [PubMed] [Google Scholar]
  9. Lehrman M. A., Schneider W. J., Brown M. S., Davis C. G., Elhammer A., Russell D. W., 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. 1987 Jan 5;262(1):401–410. [PubMed] [Google Scholar]
  10. Mullis K. B., Faloona F. A. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol. 1987;155:335–350. doi: 10.1016/0076-6879(87)55023-6. [DOI] [PubMed] [Google Scholar]
  11. Retief A. E., Kotze M. J., Oosthuizen C. J. Identification of gene mutations allows for the molecular diagnosis of familial hypercholesterolemia. S Afr Med J. 1989 Aug 5;76(3):121–121. [PubMed] [Google Scholar]
  12. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  13. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Seftel H. C., Baker S. G., Sandler M. P., Forman M. B., Joffe B. I., Mendelsohn D., Jenkins T., Mieny C. J. A host of hypercholesterolaemic homozygotes in South Africa. Br Med J. 1980 Sep 6;281(6241):633–636. doi: 10.1136/bmj.281.6241.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Südhof T. C., Goldstein J. L., Brown M. S., Russell D. W. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985 May 17;228(4701):815–822. doi: 10.1126/science.2988123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Yamamoto T., Bishop R. W., Brown M. S., Goldstein J. L., Russell D. W. Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit. Science. 1986 Jun 6;232(4755):1230–1237. doi: 10.1126/science.3010466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Yamamoto T., Davis C. G., Brown M. S., Schneider W. J., Casey M. L., Goldstein J. L., Russell D. W. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. doi: 10.1016/0092-8674(84)90188-0. [DOI] [PubMed] [Google Scholar]
  18. van der Westhuyzen D. R., Coetzee G. A., Demasius I. P., Harley E. H., Gevers W., Baker S. G., Seftel H. C. Low density lipoprotein receptor mutations in South African homozygous familial hypercholesterolemic patients. Arteriosclerosis. 1984 May-Jun;4(3):238–247. doi: 10.1161/01.atv.4.3.238. [DOI] [PubMed] [Google Scholar]

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