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Research Article Free access | 10.1172/JCI1122

Dual mechanisms for the low plasma levels of truncated apolipoprotein B proteins in familial hypobetalipoproteinemia. Analysis of a new mouse model with a nonsense mutation in the Apob gene.

E Kim, CM Cham, MM Véniant, P Ambroziak, and SG Young

Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.

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Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.

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Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.

Find articles by Véniant, M. in: JCI | PubMed | Google Scholar

Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.

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Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.

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Published March 15, 1998 - More info

Published in Volume 101, Issue 6 on March 15, 1998
J Clin Invest. 1998;101(6):1468–1477. https://doi.org/10.1172/JCI1122.
© 1998 The American Society for Clinical Investigation
Published March 15, 1998 - Version history
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Abstract

Familial hypobetalipoproteinemia (FHbeta), a syndrome characterized by low plasma cholesterol levels, is caused by mutations in the apo-B gene that interfere with the synthesis of apo-B100. FHbeta mutations frequently lead to the synthesis of a truncated form of apo-B, which typically is present in plasma at > 5% of the levels of apo-B100. Although many FHbeta mutations have been characterized, the basic mechanisms causing the low plasma levels of truncated apo-B variants have not been defined. We used gene targeting to create a mutant allele that exclusively yields a truncated apo-B, apo-B83. In mice heterozygous for the Apob83 allele, plasma levels and the size and density distribution of apo-B83-containing lipoproteins were strikingly similar to those observed in humans with FHbeta and an apo-B83 mutation. Analysis of mice carrying the Apob83 mutation revealed two mechanisms for the low plasma levels of apo-B83. First, Apob83 mRNA levels and apo-B83 secretion were reduced 76 and 72%, respectively. Second, apo-B83 was removed rapidly from the plasma, compared with apo-B100. This mouse model provides a new level of understanding of FHbeta and adds new insights into apo-B metabolism.

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