Abstract
The molecular basis of familial hypercholesterolemia (FH) in three families of Spanish descent from La Habana was investigated by the candidate gene approach. The Arg3500Gln mutation of apolipoprotein B-100 was not found. Identification of low density lipoprotein receptor (LDLR) gene haplotypes segregating with FH guided the characterisation of three point mutations by automated sequencing. One, a Val408→Met missense mutation, a founder mutation in Afrikaner FH patients, was recurrent, being associated with a distinct DNA haplotype. The other two, Glu256→Lys and Val776→Met missense mutations, were novel and modified highly conserved residues. These mutations were absent in normolipidemic subjects and were associated in heterozygous carriers with twice the cholesterol levels observed in noncarriers. Noticeably, cardiovascular complications were rarely observed in older heterozygotes, even in those with the Afrikaner FH-2 mutation. These findings confirm the molecular heterogeneity of LDLR gene mutations causing FH and the variability of their expression across different populations.
Similar content being viewed by others
References
Cavanaugh JA, Easteal S (1991) A HaeIII polymorphism in the 3′ untranslated region of the low density lipoprotein receptor (LDLR) gene. Nucleic Acids Res 19:6663
Figueiredo MS, Dos Santos JE, Alberto FL, Zago MA (1992) High frequency of the Lebanese allele of the LDLr gene among Brazilian patients with familial hypercholesterolemia. J Med Genet 29:813–815
Gonzalez R, Ballester JM, Estrada M, Lima F, Martinez G, Wade M, Colombo B, Vento R (1976) A study of the genetical structure of the cuban population: red cell and serum biochemical markers. Am J Hum Genet 28:585–596
Graadt Van Roggen JF, Van Der Westhuyzen DR, Marais AD, Gevers W, Coetzee GA (1991) LDL receptor founder mutations in Afrikaner familial hypercholesterolemic patients: a comparison of two geographic areas. Hum Genet 88:204–208
Hansen PS, Rüdiger N, Tybjærg-Hansen A, Faergeman O, Gregersen N (1991) Detection of the apo B-3500 mutation (glutamine for arginine) by gene amplification and cleavage with MspI. J Lipid Res 32: 1229–1233
Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548
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
Hobbs HH, Russell DW, Brown MS, Goldstein JL (1990) The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 24:133–170
Hobbs HH, Brown MS, Goldstein JL (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1:445–466
Kotze MJ, De Villiers WJS, Steyn K, Kriek JA, Marais AD, Langenhoven E, Herbert JF, Graadt Van Roggen JF, Van Der Westhuyzen DR, Coetzee GA (1993) Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations. Arterioscler Thromb 13:1460–1468
Leitersdorf E, Van Der Westhuyzen DR, Coetzee GA, Hobbs HH (1989) Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners. J Clin Invest 84:954–961
Loux N, Saint Jore B, Collod G, Dairou F, Benlian P, Truffert J, Dastugue B, Douste Blazy P, De Gennes JL, Junien C, Boileau C (1992) Screening for new mutations in the LDL receptor gene in seven French familial hypercholesterolemia families by the single strand conformation polymorphism. Hum Mutat 1:325–332
Mehta KD, Chen W-J, Goldstein JL, Brown MS (1991) The low density lipoprotein receptor in Xenopus laevis. Five domains that resemble the human receptor. J Biol Chem 266:10406–10414
Moorjani s, Roy M, Torres A, Bétard C, Gagné C, Lambert M, Brun D, Davignon J, Lupien P (1993) Mutations of low-density-lipoprotein receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolemia. Lancet 341:1303–1306
Saint-Jore B, Loux N, Junien C, Boileau C (1993) Two new polyorphisms in the coding sequence of the LDL receptor (LDLR) gene. Hum Genet 91:511–512
Schuster H, Fischer HJ, Keller C, Wolfram G, Zöllner N (1993) Identification of the 408 valine to methionine mutation in the low density lipoprotein receptor in a German family with familial hypercholesterolemia. Hum Genet 91:287–289
Slimane MN, Pousse H, Maatoug F, Hammami M, Ben Farhat MH (1993) Phenotypic expression of familial hypercholesterolemia in Central and Southern Tunisia. Atherosclerosis 104:153–158
Soutar AK (1991) A polymorphism in exon 2 of the human LDL-receptor gene (LDLR). Nucleic Acids Res 19:4314
Sun XM, Patel DD, Webb JC, Knight BL, Fan L-M, Cai H-J, Soutar AK (1994) Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype. Arterioscler Thromb 14:85–94
Top B, Van Der Zee A, Havekes LM, Van't Hooft F, Frants RR (1993) Identification of a splice-site mutation in the low density lipoprotein receptor gene by denaturing gradient gel electrophoresis. Hum Genet 89:480–484
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pereira, E., Ferreira, R., Hermelin, B. et al. Recurrent and novel LDL receptor gene mutations causing heterozygous familial hypercholesterolemia in La Habana. Hum Genet 96, 319–322 (1995). https://doi.org/10.1007/BF00210415
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00210415