Abstract
We have identified a new truncation of apoB in a large kindred with hypobetalipoproteinemia that arose by an ambiguous deletion of one of four different groups of base-pairs. Eleven affected members of the kindred had total cholesterols (C) of 114 +/- 28, LDL-Cs of 46 +/- 21, and apoBs of 47 +/- 25 (all in mg/dl, mean +/- SD). These levels were lower (P < 0.0001) than in 15 unaffected relatives. On Western blotting, apoB-100 and a second major band corresponding to apoB-52 were seen in the affected individuals. The majority of the plasma apoB-52 was associated with a smaller than normal low density lipoprotein (LDL) particle. The molecular basis for this apoB-52 truncation is a 5-bp deletion, converting the sequence between cDNA nucleotide 7276 and 7283 from 5'-AAGTTAAG-3' into the mutant sequence 5'-AAG-3'. This results in a frameshift starting at amino acid residue 2357 and a termination codon at amino acid residue 2362. Deletion of one of four different groups of five consecutive bases, i.e., AAGTT, AGTTA, GTTAA, and TTAAG, all result in the same mutant sequence. Thus, the precise deletion is ambiguous. We propose that a misaligned pairing mechanism involving repeat sequences is compatible with this deletion mutation. We have noted similar ambiguous deletions associated with apoB-37, apoB-40, and a number of single base deletions and some may also be explained by a misaligned pairing mechanism. Small ambiguous deletions appear to constitute a major proportion of the apoB gene mutation spectrum suggesting that it may be a suitable model for studying the mechanisms of such mutations.
Highlights
IntroductionThe molecular basis for this apolipoprotein B (apoB)-52 truncation is a 5-bp deletion, converting the sequence between cDNA nucleotide 7276 and 7283 from 5'-AAGTTAAG-3' into the mutant sequence 5'-AAG-3'
At the gene level, truncated forms of apolipoprotein B (apoB) have arisen in a number of ways: I) by a nonsense mutation converting a codon for a n amino acid into a termination codon; 2) by deletion of a large part of the gene; 3) by a point mutation or a deletion involving a n introdexon splicing site; and 4) by small single or multi-base deletions leading to a frameshift and a premature termination codon
< 5th percentile for his age, race, and sex. On immunoblotting of his plasma, apoB-100 was present as the predominant form of apoB (Fig. 1).In addition, an unusual apoB, apoB-52 was identified
Summary
The molecular basis for this apoB-52 truncation is a 5-bp deletion, converting the sequence between cDNA nucleotide 7276 and 7283 from 5'-AAGTTAAG-3' into the mutant sequence 5'-AAG-3'. We have noted similar ambiguous deletions associated with apoB-37, apoB-40, and a number of single base deletions and some may be explained by a misaligned pairing mechanism. Apolipoprotein B-52 mutation associated with hypobetalipoproteinemia is compatible with a misaligned pairing deletion mechanism. At the gene level, truncated forms of apoB have arisen in a number of ways: I) by a nonsense mutation converting a codon for a n amino acid into a termination codon; 2) by deletion of a large part of the gene; 3) by a point mutation or a deletion involving a n introdexon splicing site; and 4) by small single or multi-base deletions leading to a frameshift and a premature termination codon. Because of the ambiguous nature of this mutation, we analyzed other mutations described for the apoB gene and surprisingly found several others to be ambiguous
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