Summary
Familial hypercholesterolemia (FH) results from mutations in the low density lipoprotein (LDL) receptor gene. It has been shown that restriction fragment length polymorphisms (RFLPs) associated with this gene may be used for family and population studies. The present investigation is a population-based study of 19 Jewish families with hypercholesterolemia representing 9 different countries of origin. Ten RFLP sites were used to construct 24 different haplotypes from 112 chromosomes. These haplotypes vary in frequency from 0.9% to 28.6%. Five previously undescribed haplotypes, which comprise 8.1% of the sample, are reported here. The six most common haplotypes account for 70% of the sample. Segregation analysis reveals that, in Israel, distinct LDL receptor haplotypes are associated with hypercholesterolemia in 12 (63%) out of the 19 Jewish families. Five LDL receptor haplotypes co-segregate with hypercholesterolemia. Two of these haplotypes seem to be unique to specific population groups in Israel and may therefore represent founder mutations.
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Aalto-Setala K, Helve E, Kovanen PT, Kontula K (1989) Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxyl-terminal part of the receptor and creates an internalization-defective phenotype. J Clin Invest 84:499–505
Boerwinkle E, Xiong W, Fourest E, Chan L (1989) Rapid typing of tandemly repeated hypervariable loci by the polymerase chain reaction: application to the apolipoprotein B 3′ hypervariable region. Proc Natl Acad Sci USA 86:212–216
Botstein D, White RL, Skolnick M, Davis RW (1980) Construction of genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet 32:314–331
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 18:499–502
Goldstein JL, Brown MS (1989) Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1215–1250
Goodman RM (1979) A perspective on genetic diseases among the Jewish people. In: Goodman RM, Motulsky AG (eds) Genetic diseases among Ashkenazi Jews. Raven Press, New York, 1–17
Hegele RA, Huang LS, Herbert P, Blum CR, Buring JL, Hennekens CH, Breslow JL (1986) Apolipoprotein B-gene polymorphism associated with myocardial infarction. N Engl J Med 315:1509–1515
Hegele RA, Plaetke R, Lalouel JM (1990) Linkage disequilibrium between DNA markers at the low-density lipoprotein receptor gene. Genet Epidemiol 7:69–81
Hill WG (1974) Estimation of linkage disequilibrium in randomly mating populations. Heredity 33:229–239
Hobbs HH, Brown MS, Goldstein JL, Russell DW (1986) Deletion of exon encoding cysteine-rich repeat of LDL receptor alters its binding specificity in a subject with familial hypercholesterolemia. J Biol Chem 261:13114–13120
Hobbs HH, Leitersdorf E, Leffert CC, Cryer DR, Brown MS, Goldstein JL (1989) Evidence for a dominant gene that suppresses hypercholesterolemia in a family with defective low density lipoprotein receptors. J Clin Invest 84:656–664
Khachadurian AK, Uthman SB (1973) Experiences with the homozygous cases of familial hypercholesterolemia. Nutr Metab 15:132–140
Kotze MJ, Langenhoven E, Warnich L, Plessis LD, Marx MP, Oosthuizen CJJ, Relief AE (1989) The identification of Iwo low-densily lipoprolein receptor gene mulalions in Soulh African familial hypercholesterolemia. S Afr Med J 76:399–401
Leilersdorf E, Chakravarli A, Hobbs HH (1989a) Polymorphic haplotypes at the LDL receptor locus. Am J Hum Genet 44:409–421
Leitersdorf E, Westhuyzen DR van der, Coetzee GA, Hobbs HH (1989b) Two common low density lipoprotein gene mutations cause familial hypercholesterolemia in Afrikaners. J Clin Invest 84:954–961
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
Lehrman MA, Schneider WJ, Brown MS, Davis CG, Elhammer A, Russell DW, Goldstein JL (1987) The Lebanese allele at the LDL receptor gene locus: nonsense mutation produces truncated receptor that is retained in the endoplasmic reticulum. J Biol Chem 262:401–410
Ludwig EH, Blackhart VR, Pierotti L, Caiati L, Fortier C, Knott T, Scott J, Mahley RW, Levy-Wilson B, McCarthy BJ (1987) DNA sequence of the human apolipoprotein B gene. DNA 6:363–372
Ludwig EH, Friedl W, McCarthy BJ (1989) High resolution analysis of a hypervariable region in the human apolipoprotein B gene. Am J Hum Genet 45:458–464
Meiner V, Landsberger D, Berkman N, Reshef A, Segal P, Seftel HC, Westhuyzen DR van der, Jeenah MS, Coetzee GA, Leitersdorf E (1991) A common Lithuanian mutation causing familial hypercholesterolemia in Ashkenazi Jews. Am J Hum Genet 49:443–449
Montefiore M (ed) (1839) A census of the Jews of Eretz Israel. The Dinur Center, The Hebrew University, Jerusalem
Moorjani S, Roy M, Gagne C, Davignon J, Brun D, Toussaint M, Lambert M, Campeau L, Blaichman S, Lupien P (1989) Homozygous familial hypercholesterolemia among French-Canadians in Quebec Province. Arteriosclerosis 9:212–216
Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491
Seftel HC, Baker SG, Sandier MP, Forman MB, Joffe BI, Mendelsohn D, Jenkins T, Mieny C (1980) A host of hypercholesterolemic homozygotes in South Africa. BMJ 281:633–636
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
Southern E (1975) Detection of specific sequences among DNA fragments separated by electrophoresis. J Mol Biol 98:503–517
Weir BS, Hill WG (1986) Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet 38:776–778
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Berkman, N., Weir, B.S., Pressman-Schwartz, S. et al. Haplotype analysis at the low density lipoprotein receptor locus: application to the study of familial hypercholesterolemia in Israel. Hum Genet 88, 405–410 (1992). https://doi.org/10.1007/BF00215674
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DOI: https://doi.org/10.1007/BF00215674