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 APO-B GENE

Familial hypobetalipoproteinemia (FH beta), a syndrome characterized b y low plasma cholesterol levels, is caused by mutations in the apo-B g ene that interfere with the synthesis of apo-B100, FH beta mutations f requently lead to the synthesis of a truncated form of apo-B, which ty pically is present in plasma at < 5% of the levels of apo-B100, Althou gh many FH beta mutations have been characterized, the basic mechanism s causing the low plasma levels of truncated apo-B variants have not b een defined. We used gene targeting to create a mutant allele that exc lusively yields a truncated apo-B, apo-B83, In mice heterozygous for t he Apob(83) allele, plasma levels and the size and density distributio n of apo-B83-containing lipoproteins were strikingly similar to those observed in humans with FH beta and an apo-B83 mutation, Analysis of m ice carrying the Apob(83) mutation revealed two mechanisms for the low plasma levels of apo-B83. First, Apob(83) mRNA levels and apo-B83 sec retion were reduced 76 and 72%, respectively. Second, apo-B83 was remo ved rapidly from the plasma, compared with apo-B100, This mouse model provides a new level of understanding of FH beta and adds new insights into apo-B metabolism.