A gene-targeted mouse model for familial hypobetalipoproteinemia. Low levels of apolipoprotein B mRNA in association with a nonsense mutation in exon 26 of the apolipoprotein B gene.
Familial hypobetalipoproteinemia, a syndrome characterized by abnormally low plasma levels of low density lipoprotein cholesterol, is caused by mutations in the apolipoprotein (apo) B gene that interfere with the synthesis of a full-length apoB100. In many cases of familial hypobetalipoproteinemia, nonsense or frameshift mutations result in the synthesis of a truncated apoB protein. To understand why these mutations result in low plasma cholesterol levels, we used gene targeting in mouse embryonic stem cells to introduce a nonsense mutation (N1785Stop) into exon 26 of the mouse Apob gene. The sole product of this mutant Apob allele was a truncated apoB, apoB39. Mice homozygous for this "apoB39-only" (Apob39) allele had low plasma levels of apoB39 and markedly reduced plasma levels of very low density lipoprotein and low density lipoprotein cholesterol when fed a high fat diet. Analysis of liver and intestinal RNA from heterozygous apoB39-only mice revealed that the Apob39 mRNA levels were 60-70% lower than those from the wild-type allele. Interestingly, apoB39 was not cleared as rapidly from the plasma as apoB48. The apoB39-only mice provide new insights into the mechanisms of familial hypobetalipoproteinemia and the structural features of apoB that are important for lipoprotein metabolism.
Kim
E
E
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.
Ambroziak
P
P
Véniant
M M
MM
Hamilton
R L
RL
Young
S G
SG
D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D001483:Base Sequence; D002678:Chimera; D002784:Cholesterol / Q000097:blood; D018389:Codon, Nonsense; D018388:Codon, Terminator; D004041:Dietary Fats; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006995:Hypobetalipoproteinemias / Q000097:blood / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D013234:Stem Cells
D001055:Apolipoproteins B; D018389:Codon, Nonsense; D018388:Codon, Terminator; D004041:Dietary Fats; D008074:Lipoproteins; D009838:Oligodeoxyribonucleotides; D002784:Cholesterol