Skip to main content
Log in

Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia

  • Review
  • Published:
The clinical investigator Aims and scope Submit manuscript

Summary

Familial defective apolipoprotein B-100 (FDB) is a recently identified dominantly inherited genetic disorder characterized by a decreased binding of low density lipoprotein (LDL) to the LDL receptor due to defective apo B-100. FD B is caused by a G to A mutation at nucleotide 10 708 in exon 26 of the apo B gene creating a substitution of glutamine for arginine in the codon for amino acid 3500. The arginine(3500) → glutamine mutation has been observed in several populations in North America and Europe with a similar frequency of approximately 1/500 to 1/700. Haplotype analysis has demonstrated that the arginine(3500) → glutamine mutation occurs on the same chromosomal background. The fact that all individuals with FDB are of Caucasian extraction implies that the mutation has its origin in this population. The arginine(3500) → glutamine mutation has a profound impact of varying strength on the plasma LDL cholesterol level, leading to heterogeneous clinical expression comparable to “classic” familial hypercholesterolemia (FH) caused by a defective LDL receptor: tendon xanthoma, premature atherosclerosis and arcus lipoides. The present data suggest that the combination of these clinical features is no longer appropriate for the diagnosis of LDL-receptor-defective FH, but may be a common feature of a defective LDL receptor pathway originating either from defective LDL receptors or from malfunctioning ligand apo B-100.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

apo B-100:

apolipoprotein B-100

CAD:

coronary artery diseae

FDB:

familial defective apolipoprotein B100

FH:

familial hypercholesterolemia

HDL:

high density lipoprotein

HL:

hyperlipidemia

LDL:

low density lipoprotein

PAD:

peripheral artery disease

PCR:

polymerase chain reaction

VLDL:

very low density lipoprotein

References

  1. Botstein D, White RL, Skolnick M, Davis RW (1980) Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet 32:314–331

    Google Scholar 

  2. Brown MS, Goldstein JL (1986) A receptor mediated pathway for cholesterol homeostasis. Science 232:34–47

    Google Scholar 

  3. Conner BJ, Reyes AA, Morin C, Itakura K, Teplitz RL, Wallace RB (1983) Detection of sickle-cell β s-globin allele by hybridization with synthetic oligonucleotides. Proc Natl Acad Sci USA 80:278–272

    Google Scholar 

  4. Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155

    Google Scholar 

  5. Corsini A, Fantappie S, Granata A, Bernini F, Catapano AL, Fumagalli R, Romano L, Romano C (1989) Binding defective low-density lipoprotein in family with hypercholesterolemia, Lancet i:623

    Google Scholar 

  6. Corsini A, Mazzotti M, Fumagalli R, Catapano AL, Romano L, Romano C (1991) Poor response to simvastatin in familial defective apolipoprotein B-100. Lancet i:305

    Google Scholar 

  7. Elovson J, Jacobs JC, Schumaker VN, Puppione DL (1985) Molecular weights of apoprotein B obtained from human low-density lipoprotein (apolipoprotein B-PI) and from rat very-low density lipoprotein (apoprotein B-PIII). Biochemistry 24:1569–1578

    Google Scholar 

  8. Friedl W, Ludwig EH, Balestra ME, Arnold KS, Paulweber B, Sandhofer F, McCarthy BJ, Innerarity T (1991) Apolipoprotein B gene mutations in Austrian subjects with heart disease and their kindred. Arterioscler Thromb 11:371–378

    Google Scholar 

  9. Frostegdrd J, Hamsten A, Gidlund M, Nilsson J (1990) Low density lipoprotein induced growth of U 937 cells: a novel method to determine the receptor binding of low density lipoprotein. J Lipid Res 31:37–43

    Google Scholar 

  10. Gavish D, Brinton EA, Breslow JL (1989) Heritable allelespecific differences in amounts of apo B and low-density lipoproteins in plasma. Science 244:72–76

    Google Scholar 

  11. Geisel J, Schleifenbaum T, Weißhaar B, Oette K (1991) Rapid diagnosis of familial defective apolipoprotein B-100. Eur J Clin Chem Clin Biochem 29:305–309

    Google Scholar 

  12. Gofman JW, Glazier F, Tamplin A, Strisower B, de Lalla O (1954) Lipoproteins, coronary heart disease, and atherosclerosis. Physiol Rev 34:589–607

    Google Scholar 

  13. Goldstein JL, Brown MS (1989) Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds), The metabolic basis of inherited disease. McGraw-Hill, New York:1215–1250

    Google Scholar 

  14. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR (1977) Predicting coronary heart disease in middle-aged and older persons. The Framingham Study. JAMA 238:497–499

    Google Scholar 

  15. Hämäläinen T, Palotic A, Aalto-Setälä K, Kontula K, Tikkanan MJ (1990) Absence of familial defective apolipoprotein B-100 in Finnish patients with elevated serum cholesterol. Atherosclerosis 82:177–183

    Google Scholar 

  16. Hansen PS, Rüdiger N, Tybjxrg-Hansen A, Fægerman O, Gregersen N (1991) Detection of the apo B-3500 mutation (glutamine for arginine) by gene amplification and cleavage with Mspl. J Lipid Res 32:1229–1233

    Google Scholar 

  17. Henze K, Wallmüller-Strycker A, Bauer M, Barth C, Wolfram G, Zöllner N (1981) Cholesterin and Triglyceride im Serum einer Münchner Bevölkerungsgruppe: Beziehungen zur Alter und Geschlecht. J Clin Chem Clin Biochem 19:1013–1019

    Google Scholar 

  18. Hobbs HH, Brown MS, Russell DE, Davignon J, Goldstein JL (1987) Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia. N Engl J Med 317:734–737

    Google Scholar 

  19. Hobbs HH, Leitersdorf E, Goldstein JL, Brown MS, Russel DW (1989) Multiple crin-mutations in familial hypercholesterolemia: evidence for 13 alleles, including four deletions. J Clin Invest 81:909–917

    Google Scholar 

  20. Houlston RS, Turner PR, Revill J, Lewis B, Humphries SE (1988) The fractional catabolic rate of low density lipoprotein in normal individuals is influenced by variation in the apolipoprotein B gene: a preliminary study. Atherosclerosis 71:81–85

    Google Scholar 

  21. Innerarity TL, Balestra ME, Arnold KS, Mahley RW, Vega GL, Grundy SM, Young SG (1988) Isolation of defective receptor-binding low density lipoproteins from subjects with familial defective apolipoprotein B-100. Arteriosclerosis 8:551a

  22. Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL, Grundy SM, Friedl W, Davignon J, McCarthy BJ (1990) Familial defective apolipoprotein B-100: a mutation of the apolipoprotein B that causes hypercholesterolemia. J Lipid Res 31:1337–1349

    Google Scholar 

  23. Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, Vega GL, Grundy SM (1987) Familial defective apoliprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 84:6919–6923

    Google Scholar 

  24. Keller C, Harders-Spengel K, Spengel F, Wieczorek A, Wolfram G, Zöllner N (1981) Serum cholesterol levels in patients with familial hypercholesterolemia confirmed by tissue culture 39:51–59

    Google Scholar 

  25. Knott TJ, Pease RJ, Powell LM, Wallis SC, Rall SC, Innerarity TL, Blackhart B, Taylor WH, Marcel Y, Milne R, Johnson D, Fuller M, Lusis AJ, McCarthy BJ, Mahley RW, Levy-Wilson B, Scott J (1986) Complete protein sequence and identification of structural domains of human apolipoprotein B. Nature 323:734–738

    Google Scholar 

  26. Lipid Research Clinics Program (1980) Population studies data book, vol 1: the prevalence study. US Department of Health and Human Services, National Institutes of Health, Washington, DC NIH publication no. 80-1527)

    Google Scholar 

  27. Ludwig EH, McCarthy GJ (1990) Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B 100. Am J Hum Genet 47:712–720

    Google Scholar 

  28. Lund-Katz S, Ibdah JA, Letizia JY, Thomas MT, Phillips MC (1988) A 13C NMR characterization of lysine residues in apolipoprotein B and their role in binding to the low density lipoprotein receptor. J Biol Chem 263:13831–13838

    Google Scholar 

  29. Lund-Katz S, Innerarity TL, Curtiss LK, Krauss RM, Philipps MC (1989) 13C-NMR evidence that substution of Gln for Arg 3500 in familial defective apo B-100 disrupts the conformation of the receptor binding domain. Arteriosclerosis 9:715a

    Google Scholar 

  30. Motti C, Funke H, Rust S, Dergunov A, Assmann G (1991) Using mutagenic polymerase chain reaction primers to detect carriers of familial defective apolipoprotein B-100. Clin Chem 37:1762–1766

    Google Scholar 

  31. Myant NB, Gallagher JJ, Knight BL, McCarthy SN, Frostegdrd J, Nilsson J, Hamsten A, Talmud PJ, Humphries SE (1991) Clinical signs of familial hypercholesterolemia in patients with familial defective apolipoprotein B-100 and normal low density lipoprotein receptor function. Arterioscler Thromb 11:691–703

    Google Scholar 

  32. Pease RJ, Milne RW, Jessup WK, Law A, Provost P, Fruchart JC, Dean RT, Marcel YL, Scott J (1990) Use of bacterial expression cloning to localize the epitopes for a series of monoclonal antibodies against apolipoprotein B-100. J Biol Chem 265:553–568

    Google Scholar 

  33. Rauh G, Keller C, Kormann B, Spengel F, Schuster H, Wolfram G, Zöllner N (1991) Familial defective apolipoprotein B-100: clinical characteristics of 54 cases. Atherosclerosis (accepted)

  34. Rauh G, Schuster H, Fischer J, Keller C, Wolfram G, Zöllner N (1991) Identification of a heterozygous compound individual with familial hypercholesterolemia and familial defective apolipoprotein B-100. Klin Wochenschr 69:320–324

    Google Scholar 

  35. Rauh G, Schuster H, Fischer J, Keller C, Wolfram G, Zöllner N (1991) Familial defective apolipoprotein B-100: haplotype analysis of the arginine(3500) → glutamine mutation. Atherosclerosis 88:219–226

    Google Scholar 

  36. Rauh G, Schuster H, Müller B, Schewe S, Keller C, Wolfram G, Zöllner N (1990) Genetic evidence from 7 families that the apolipoprotein B gene is not involved in familial combined hyperlipidemia. Atherosclerosis 83:81–87

    Google Scholar 

  37. Saiki RK, Bugawan TL, Horn GT, Mullis KB, Erlich HA (1986) Analysis of enzymatically amplified β-globin and HLADQa DNA with allelespecific oligonucleotide probes. Nature 324:163–166

    Google Scholar 

  38. Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi RG, Horn TT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with thermostable DNA polymerase. Science 239:487–491

    Google Scholar 

  39. Schuster H, Humphries S, Rauh G, Keller C, Wolfram G, Zöllner N (1990) Association of DNA haplotypes in the human LDL receptor gene with normal serum cholesterol levels. Clin Genet 38:401–409

    Google Scholar 

  40. Schuster H, Kröner KK, Keller C, Spengel FA, Wolfram G, Zöllner N (1987) Atherosclerosis of the carotid artery documented by duplex scan as a predictor of coronary artery disease. Klin Wochenschr 65:34–39

    Google Scholar 

  41. Schuster H, Rauh G, Gerl C, Keller C, Wolfram G, Zöllner N (1991) Use of DNA haplotype analysis in diagnosis of familial hypercholesterolemia in 31 German families. J Med Genet 20:865–870

    Google Scholar 

  42. Schuster H, Rauh G, Kormann B, Hepp T, Humphries S, Keller C, Wolfram G, Zöllner N (1990) Familial defective apolipoprotein B-100: comparison with familial hypercholesterolemia in 18 cases detected in Munich. Arteriosclerosis 10:577–581

    Google Scholar 

  43. Schuster H, Stiefenhofer B, Wolfram G, Keller C, Humphries S, Huber A, Zöllner N (1989) Four DNA polymorphisms in the LDL-receptor gene and their use in diagnosis of familial hypercholesterolemia. Hum Genet 82:69–72

    Google Scholar 

  44. Soria LF, Ludwig EH, Clarke HRG, Vega GL, Grundy SM, McCarthy BJA (1989) Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 86:587–591

    Google Scholar 

  45. Spengel FA, Harders-Spengel K, Keller C, Wieczorek A, Wolfram G, Zöllner N (1982) Use of fibroblast culture to diagnose and genotype familial hypercholesterolemia. Ann Nutr Metab 26:240–247

    Google Scholar 

  46. Spengel FA, Kaess B, Keller C, Kröner KK, Schreiber M, Schuster H, Zöllner N (1988) Atherosclerosis of the carotid arteries in young patients with familial hypercholesterolemia. Klin Wochenschr 66:65–68

    Google Scholar 

  47. Talmud PJ, Lloyd JK, Muller DPR, Collins DR, Scott J, Humphries SE (1988) Genetic evidence from two families that the apolipoprotein B gene is not involved in abetalipoproteinemia. J Clin Invest 82:1803–1806

    Google Scholar 

  48. Tybjærg-Hansen A, Gallagher J, Vincent J, Houlston R, Talmud P, Dunning AM, Seed M, Hamsten A, Humphries SE, Myant NB (1990) Familial defective apolipoprotein B100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases. Atherosclerosis 80:235–242

    Google Scholar 

  49. Vega GL, Grundy SM (1986) In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 78:1410–1414

    Google Scholar 

  50. Weisgraber KH, Innerarity TL, Mahley RW (1978) Role of the lysine residues of plasma lipoproteins in high affinity binding to cell surface receptors on human fibroblasts. J Biol Chem 253:9053–9062

    Google Scholar 

  51. Weisgraber KH, Innerarity TL, Newhouse YM, Young SG, Arnold KS, Krauss RM, Vega GL, Grundy SM, Mahley RW (1988) Familial defective apolipoprotein B-100: enhanced binding of monoclonal antibody MB47 to abnormal low density lipoproteins. Proc Natl Acad Sci USA 85:9758–9762

    Google Scholar 

  52. Young SG (1990) Recent progress in understanding apolipoprotein B. Circulation 82:1574–1594

    Google Scholar 

  53. Zöllner N (1964) Metabolism of steroids and carotinoids. In: Thannhauser's textbook of metabolism and metabolic disorders. Grune & Stratton, New York, 56–74

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rauh, G., Keller, C., Schuster, H. et al. Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia. Clin Investig 70, 77–84 (1992). https://doi.org/10.1007/BF00422946

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00422946

Key words

Navigation