Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3: structure and genetics of an apolipoprotein E3 variant
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A family has been described in which type III hyperlipoproteinemia is associated with apo E phenotype E3/3 (Havel, R. J., L. Kotite, J. P. Kane, P. Tun, and T. Bersot. 1983. J. Clin. Invest. 72:379-387). In the current study, the structure of apo E from the propositus of this family was determined using both protein and DNA analyses. The propositus is heterozygous for two different apo E alleles, one coding for normal apo E3 and one for a previously undescribed variant apo E3 in which arginine replaces cysteine at residue 112 and cysteine replaces arginine at residue 142. Apo E gene analysis of nine other family members spanning four generations indicated that only those five members having type III hyperlipoproteinemia possess the variant apo E3. Like the propositus, all five are heterozygous for this variant, suggesting that the disorder in this family is transmitted in a dominant fashion. The variant apo E3 was defective in its ability to bind to lipoprotein receptors, and this functional defect probably contributes to the expression of type III hyperlipoproteinemia in this family.
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Sequence analysis identified an R142C substitution in the ε4 allele (Arg112 Cys142 Arg158).
“Sequence analysis identifi ed an R142C substitution in the 4 allele (Arg112 Cys142 Arg158) ( 29 ).”
From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [29]
The Results (p. 1097) report sequencing an allele encoding Arg112 and Cys142; the paper also identifies Arg158 in its analysis of the variant. But it calls the observed product an apo E3 variant. The Discussion says it is likely, rather than established, that the variant arose through a mutation in an apo E4 allele, so the claim overstates its identification as an ε4 allele. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCertain other apoE variants are associated with a dominant mode of inheritance, i.e., heterozygosity is sufficient for expression of type III hlp.
“In contrast, certain other apoE variants are associated with a dominant mode of inheritance (5-10), i.e., heterozygosity for these apoE variants is sufficient for the expression of type III hlp.”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [5]
The mutations of apoE3(112 Cys→Arg, 142 Arg→Cys) and apoE1-Harrisburg(146 Lys→Glu) occur within a putative α-helix (residues 131-150).
“In contrast, the mutations of both apoE3(112 Cys→Arg, 142 Arg→Cys) (10) and apoE1-Harrisburg(146 Lys→Glu) (11) occur within a putative α-helix (residues 131-150) (25), which is rich in basic amino acids that are thought to provide direct ionic interaction with the acidic residues within the ligand binding domain of the LDL receptor (31).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [10]
The apoE3(112 Cys→Arg, 142 Arg→Cys) and apoE1-Harrisburg(146 Lys→Glu) mutants are defective in their interaction with the LDL receptor.
“These latter two mutants are also defective in their interaction with the LDL receptor (10, 11).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [10]
Three other apoE variants display an absolute correlation between the presence of only one allele for the variant and the occurrence of type III hyperlipoproteinemia, indicating that these mutants are associated with dominant, rather than recessive, expression of this disorder.
“In contrast to apoE2(158 Arg→Cys), three other apoE variants display an absolute correlation between the presence of only one allele for the variant and the occurrence of type III hyperlipoproteinemia, indicating that these mutants are associated with dominant, rather than recessive, expression of this disorder (2, 10, 11).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [10]
A second variant that results in a dominant mode of expression of type III hyperlipoproteinemia is apoE3(112 Cys→Arg, 142 Arg→Cys); six family members from four generations are heterozygous for this variant and express type III hyperlipoproteinemia, whereas family members lacking this variant do not express the disorder.
“A second variant that results in a dominant mode of expression of type III hyperlipoproteinemia is apoE3(112 Cys→Arg, 142 Arg→Cys) (10). Six family members from four generations are heterozygous for this variant and express type III hyperlipoproteinemia, whereas family members lacking this variant do not express the disorder (10).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [10]
There are two other apoE mutants for which dominant expression of type III hyperlipoproteinemia also appears to be the case: apoE3(112 Cys→Arg, 142 Arg→Cys) and apoE1-Harrisburg(146 Lys→Glu).
“There are two other apoE mutants for which this also appears to be the case: apoE3(112 Cys→Arg, 142 Arg→Cys) (10) and apoE1-Harrisburg(146 Lys→Glu) (11).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [10]
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Cites
Human apolipoprotein E. The complete amino acid sequence
Rall, S. C., Weisgraber, K. H., & Mahley, R. W. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34702-1 · Cited by 741 · see citing works
Self-citationZannis, V. I., & Breslow, J. L. (1981) · Biochemistry · doi:10.1021/bi00507a059 · Cited by 563 · see citing works
Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes
Zannis, V. I., Breslow, J. L., Utermann, G., Mahley, R. W., Weisgraber, K. H., Havel, R. J., Goldstein, J. L., Brown, M. S., Schonfeld, G., Hazzard, W. R., et al. (1982) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)38094-9 · Cited by 436 · see citing works
Self-citationAbnormal in vivo metabolism of apolipoprotein E4 in humans.
Gregg, R. E., Zech, L. A., Schaefer, E. J., Stark, D., Wilson, D., & Brewer, H. B. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112645 · Cited by 345 · see citing works
Rall, S. C., Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.15.4696 · Cited by 345 · see citing works
Self-citationThe receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments.
Innerarity, T. L., Friedlander, E. J., Rall, S. C., Weisgraber, K. H., & Mahley, R. W. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44180-9 · Cited by 276 · see citing works
Self-citationWardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R., & Carrell, R. W. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113096 · Cited by 159 · see citing works
Fainaru, M., Mahley, R. W., Hamilton, R. L., & Innerarity, T. L. (1982) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)38102-5 · Cited by 156 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 4
- Brown, M. S., J. L. Goldstein, and D. S. Fredrickson. 1983. Familial type 3 hyperlipoproteinemia (dysbetalipoproteinemia). In The Metabolic Basis of Inherited Disease. J. B. Stanbury, J. B. Wyn- gaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, editors. 5th ed. McGraw-Hill Book Co., New York. 655-671.
- Havel, R. J., and J. P. Kane. 1973. Primary dysbetalipoprotein- emia: predominance of a specific apoprotein species in triglyceride- rich lipoproteins. Proc. Nat!. Acad. Sci. USA. 70:2015-2019.
- Paik, Y.-K., D. J. Chang, C. A. Reardon, G. E. Davies, R. W. Mahley, and J. M. Taylor. 1985. Nucleotide sequence and structure of the human apolipoprotein E gene. Proc. Nati. Acad. Sci. USA. 82:3445-3449.
- Sanger, F., S. Nicklen, and A. R. Coulson. 1977. DNA se- quencing with chain-terminating inhibitors. Proc. Natl. Acad. Sci. USA. 74:5463-5467.
Cited by
Sorted by citations
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Self-citationMahley, R. W., & Ji, Z.-S. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33334-4 · Cited by 693 · see citing works
Self-citationMahley, R. W., Huang, Y., & Rall, S. C. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32417-2 · Cited by 447 · see citing works
Self-citationAPOE gene variants in primary dyslipidemia
Khalil, Y. A., Rabès, J.-P., Boileau, C., & Varret, M. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.05.007 · Cited by 170 · see citing works
Oikawa, S., Matsunaga, A., Saito, T., Sato, H., Seki, T., Hoshi, K., Hayasaka, K., Kotake, H., Midorikawa, H., Sekikawa, A., et al. (1997) · Journal of the American Society of Nephrology · doi:10.1681/asn.v85820 · Cited by 103 · see citing works
de Knijff, P., van den Maagdenberg, A. M., Stalenhoef, A. F., Leuven, J. A., Demacker, P. N., Kuyt, L. P., Frants, R. R., & Havekes, L. M. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115349 · Cited by 100 · see citing works
Wardell, M. R., Weisgraber, K. H., Havekes, L. M., & Rall, S. C. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)30067-5 · Cited by 80 · see citing works
Self-citationSmit, M., de Knijff, P., van der Kooij-Meijs, E., Groenendijk, C., van den Maagdenberg, A., Gevers Leuven, J., Stalenhoef, A., Stuyt, P., Frants, R., & Havekes, L. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42759-2 · Cited by 74 · see citing works
Orth, M., Weng, W., Funke, H., Steinmetz, A., Assmann, G., Nauck, M., Dierkes, J., Ambrosch, A., Weisgraber, K. H., Mahley, R. W., et al. (1999) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.19.5.1306 · Cited by 42 · see citing works
Self-citationCharacterization of a new apolipoprotein E5 variant detected in two French-Canadian subjects
Mailly, F., Xu, C., Xhignesse, M., Lussier-Cacan, S., Talmud, P., Davignon, J., Humphries, S., & Nestruck, A. (1991) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42048-6 · Cited by 36 · see citing works
FEUSSNER, G., FUNKE, H., WENG, W., ASSMANN, G., LACKNER, K. J., & ZIEGLER, R. (1992) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.1992.tb01511.x · Cited by 28 · see citing works
Mann, W. A., Lohse, P., Gregg, R. E., Ronan, R., Hoeg, J. M., Zech, L. A., & Brewer, H. B. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118096 · Cited by 28 · see citing works
Radwan, Z. H., Wang, X., Waqar, F., Pirim, D., Niemsiri, V., Hokanson, J. E., Hamman, R. F., Bunker, C. H., Barmada, M. M., Demirci, F. Y., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114618 · Cited by 27 · see citing works
Fazio, S., Horie, Y., Weisgraber, K., Havekes, L., & Rall, S. (1993) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)40736-9 · Cited by 23 · see citing works
Self-citationVezeridis, A. M., Drosatos, K., & Zannis, V. I. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m008409 · Cited by 11 · see citing works
Feussner, G., Albanese, M., & Valencia, A. (1996) · Atherosclerosis · doi:10.1016/0021-9150(96)05870-4 · Cited by 7 · see citing works
- Authors
- Rall, S. C., Newhouse, Y. M., Clarke, H. R., Weisgraber, K. H., McCarthy, B. J., Mahley, R. W., & Bersot, T. P.
- Affiliations
- Gladstone Institutes (US)
- University of California, San Francisco (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1989-04-01
- Volume
- 83
- Issue
- 4
- Pages
- 1095-1101
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC303794
- OpenAlex
- W1979447150
- Cited by
- 103
- References
- 8
- Citations by year
- 2022: 3 · 2021: 2 · 2020: 1 · 2019: 1 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 8.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- type III hyperlipoproteinemia, apolipoprotein E, protein structure, genetic analysis, dominant inheritance, familial hyperlipidemia
- MeSH terms
- Adult, Aged, Amino Acid Sequence, Apolipoproteins E, Base Sequence, Child, Female, Genetic Testing, Humans, Hyperlipoproteinemia Type IV, Isoelectric Focusing, Male, Middle Aged, Molecular Sequence Data, Phenotype, Receptors, Cell Surface, Genetic Variation, Low Density Lipoprotein Receptor-Related Protein-1
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