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The molecular basis of a familial apoE deficiency. An acceptor splice site mutation in the third intron of the deficient apoE gene.

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Cladaras, C., Hadzopoulou-Cladaras, M., Felber, B.K., Pavlakis, G., Zannis, V.I.·1987·Journal of Biological Chemistry
DOI 10.1016/s0021-9258(18)61655-2
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Abstract

The molecular basis of the familial apoE deficiency was investigated by gene cloning and comparative expression studies of the normal and the deficient apoE gene. For the latter studies the apoE genes were placed under the control of the mouse metallothionein I promoter in a bovine papilloma virus vector. The studies showed that in the normal gene the mouse metallothionein I promoter directs the synthesis of normal apoE mRNA and protein. In contrast, in the deficient apoE gene the same promoter directs the synthesis of two abnormal apoE mRNA forms, which are similar to those observed in the peripheral blood monocyte macrophage cultures of the patient. Restriction analysis of the cloned gene and partial DNA sequence has shown an A to G substitution in the penultimate 3' nucleotide of the third intron of the apoE gene. This single base substitution abolishes the correct 3' splice site thus creating two abnormally spliced mRNA forms. The smaller form contains 53 nucleotides and the larger form contains the entire third intron of the apoE gene. Both of these mRNA species contain chain termination codons within the intronic sequence and code for short apoE peptides that are not detectable by gel electrophoretic techniques. These findings show that this form of familial apoE deficiency results from a point mutation in the 3' splice junction of the third intron of the apoE gene. Furthermore, the expression system we have employed to study apoE deficiency can be utilized to analyze a broad spectrum of genetic diseases associated with mRNA processing mutations.

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  • Two cases with no reported mutation site and homozygotes for APOE deficiency due to variant in the intron 3 acceptor site (c.237-2A>G) and APOE deficiency (Glu79fsTer98) with almost no detectable apoE have been reported to cause severe type III HLP, including various xanthomas as well as palmar linear xanthomas.

    “Two cases with no reported mutation site and homozygotes for APOE deficiency due to variant in the intron 3 acceptor site (c.237-2A>G)32, 33) and APOE deficiency (Glu79fsTer98)34) with almost no detectable apoE have been reported to cause severe type III HLP, including various xanthomas as well as palmar linear xanthomas (Table 1).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [33]

  • Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes.

    “Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes27, 29-40).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [33]

  • In one other patient with familial apo E deficiency, a point mutation in the 3' splice junction of the third intron of the apo E gene was found; as a consequence, apo E mRNA species contained chain termination codons within the intronic sequence coding for short apo E peptides that were not detectable by gel electrophoretic techniques.

    “In one case a point mutation in the 3' splice junction of the third intron of the apo £ gene was found.13As a consequence, apo E mRNA species of this subject contained chain termination codons within the intronic sequence coding for short apo E peptides that were not detectable by gel electrophoretic techniques.'3”

    From Severe xanthomatosis associated with familial apolipoprotein E deficiency. (1996) · cites this paper as [13]

Cites

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Research works printed but not linked: 2

  1. Zannis, 1984, Adv. Human Genet., 14, 125
  2. Pavlakis, 1983, Recent Prog. Hormone Res., 39, 353

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Authors
Cladaras, C., Hadzopoulou-Cladaras, M., Felber, B. K., Pavlakis, G., & Zannis, V. I.
Affiliations
Boston University (US)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1987-02
Volume
262
Issue
5
Pages
2310-2315
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/s0021-9258(18)61655-2
OpenAlex
W1595513249
Cited by
92
References
53
Citations by year
2025: 1 · 2020: 1 · 2019: 1 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 1
FWCI
2.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (HL-33952)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
apolipoprotein E, 3' splice site mutation, alternative splicing, aberrant mRNA splicing
MeSH terms
Animals, Apolipoproteins E, Base Sequence, DNA Restriction Enzymes, Gene Expression Regulation, Humans, Hyperlipoproteinemia Type III, Introns, Mutation, Nucleic Acid Hybridization, RNA Splicing, Mice

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