Nucleotide sequence encoding the carboxyl-terminal half of apolipoprotein B from spontaneously hypercholesterolemic pigs

Purtell, C.; Maeda, Nobuyo; Ebert, DL; Kaiser, M. E.; Lund‐Katz, Sissel; Sturley, SL; Kodoyianni, Voula; Grunwald, Kurt A. A.; Nevin, DN; Aiello, RJ

doi:10.1016/s0022-2275(20)36962-5

Cited by 10 publications

(2 citation statements)

References 47 publications

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“…Receptor binding studies revealed that these particles bound to the LDL receptor in cultured pig skin fibroblasts with one-sixth the affinity of normal pig LDL (7). The nucleotide sequence encoding the carboxyl-terminal half of the apoB from Lpb5 animals revealed 13 amino acid polymorphisms (8)(9)(10). However, the Lpb5 apoB contains a unique haplotype consisting of Asp 3164 and Ala 3447 (10).…”

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“…The nucleotide sequence encoding the carboxyl-terminal half of the apoB from Lpb5 animals revealed 13 amino acid polymorphisms (8)(9)(10). However, the Lpb5 apoB contains a unique haplotype consisting of Asp 3164 and Ala 3447 (10). As these two amino acids lie within the putative receptor binding domain of apoB, it is likely that this combination of amino acids is responsible for the lowered receptor binding affinity of Lpb5 apoB.…”

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Identification of a novel Arg→Cys mutation in the LDL receptor that contributes to spontaneous hypercholesterolemia in pigs

Grunwald

Schueler

Uelmen

et al. 1999

Journal of Lipid Research

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We previously carried out genetic and metabolic studies in a partially inbred herd of pigs carrying cholesterol-elevating mutations. Quantitative pedigree analysis indicated that apolipoprotein (apo)B and a second major gene were responsible for the hypercholesterolemia in these animals. In this study, we assessed LDL receptor function by three different methods: ligand blots of liver membranes using ␤ -very low density lipoprotein (VLDL) as a ligand; low density lipoprotein (LDL)-dependent proliferation of T-lymphocytes; and direct binding of 125 I-labeled LDL to cultured skin fibroblasts. All three methods demonstrated that LDL receptor ligands bound with decreased affinity to the LDL receptor in these animals. In skin fibroblasts from the hypercholesterolemic pigs, the K d of binding was about 4-fold higher than in cells from normal pigs. The cDNA of the pig LDL receptor from normal and hypercholesterolemic pigs was isolated and sequenced. We identified a missense mutation that results in an Arg ¨ Cys substitution at the position corresponding to Arg 94 of the human LDL receptor. The mutation is in the third repeat of the ligand binding domain of the receptor. By single-stranded conformational polymorphism (SSCP) analysis, we studied the relationship between LDL receptor genotype and plasma cholesterol phenotype. In contrast to humans, the hypercholesterolemia associated with the LDL receptor mutation in pigs was expressed as a recessive trait. The LDL receptor mutation made a far more significant contribution to hypercholesterolemia than did the apoB mutation, consistent with observations made in human subjects with apoB mutations. Within each genotypic group (mutated apoB or mutated receptor), there was a wide range in plasma cholesterol. As the animals were on a well-controlled low-fat diet, this suggests that there are additional genetic factors that influence the penetrance of cholesterol-elevating mutations. -Grunwald, K. A

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confidence: 99%

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confidence: 99%

Identification of a novel Arg→Cys mutation in the LDL receptor that contributes to spontaneous hypercholesterolemia in pigs

Grunwald

Schueler

Uelmen

et al. 1999

Journal of Lipid Research

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Merging Metabolomics, Genetics, and Genomics in Livestock to Dissect Complex Production Traits

Fontanesi

2016

Systems Biology in Animal Production and Health, Vol. 1

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The binding of animal low-density lipoproteins to human apolipoprotein(a)

Trieu

McConathy

1995

Biochemical Journal

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Lipoprotein(a) [Lp(a)] is a risk factor for coronary artery disease. It is composed of lipids and apolipoprotein(a) [apo(a)] linked to apolipoprotein B (apoB) by a disulphide bond between Cys-4057 of apo(a)'s kringle 36 and possibly Cys-3734 of apoB. We call this the covalent apo(a): apoB-Lp interaction, to distinguish it from the non-covalent apo(a)/Lp(a): apoB-Lp interaction, which is probably mediated by apo(a)'s kringle 33 and residues 3304-3317 of apoB. The non-covalent interaction could be the initial interaction which brings apo(a) and apoB together prior to covalent linkage and Lp(a) formation. The non-covalent apo(a)/Lp(a)-binding site on apoB is evolutionarily more ancient than the covalent apo(a)-binding site on apoB. Both human and non-human low-density lipoproteins (LDLs) bind non-covalently to human apo(a)/Lp(a); however, only rabbit and human LDLs bind covalently to human apo(a). The non-covalent interaction between mouse LDL and human apo(a)/Lp(a) has a Kd of (1.7 +/- 1.33) x 10(-7) M (n = 3). This explains the co-localization of human apo(a) and mouse apoB in the atherosclerotic lesions of human apo(a) transgenic mice and supports our hypothesis that the non-covalent interaction is a contributing factor to apo(a) atherogenicity.

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Nucleotide sequence encoding the carboxyl-terminal half of apolipoprotein B from spontaneously hypercholesterolemic pigs

Cited by 10 publications

References 47 publications

Identification of a novel Arg→Cys mutation in the LDL receptor that contributes to spontaneous hypercholesterolemia in pigs

Identification of a novel Arg→Cys mutation in the LDL receptor that contributes to spontaneous hypercholesterolemia in pigs

Merging Metabolomics, Genetics, and Genomics in Livestock to Dissect Complex Production Traits

The binding of animal low-density lipoproteins to human apolipoprotein(a)

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