We emined a mutant human apolipoprotein B (apoB) allele that causes hypobetalipoproteinemia and has a single cytosine deletion in exon 26. This fameshift mutation was associated with the synthesis of a truncated apoB protein of the predicted size; however, studies in human subjects and minigene expression studies in cultured cells indicated that the mutant allele also yielded a full-length apoB protein. The 1-base-pair deletion in the mutant apoB allele created a stretch of eight consecutive adenines. To understand the mechanism whereby the mutant apoB allele yielded a full-length apoB protein, the cDNA from cells transfected with the mutant apoB minigene expression vector was examined. Splicing of the mRNA was normal; however, 11% of the cDNA clones had an additional adenine within the stretch of eight adenines, yielding nine consecutive adenines. The insertion of the extra adenine, presumably during apoB gene transcription, is predicted to restore the correct apoB reading frame, thereby permitting the synthesis of a full-length apoB protein. In 1979, Steinberg et al. (1) characterized an unusual kindred (the H.J.B. kindred) with asymptomatic familial hypobetalipoproteinemia. Their studies suggested that H.J.B. and two of his siblings, who had extremely low levels of low density lipoprotein (LDL) cholesterol (<8 mg/dl), might be homozygotes for hypobetalipoproteinemia, whereas several other members of the kindred with moderately reduced LDLcholesterol levels (29-62 mg/dl) were postulated to be heterozygotes. In 1987, Young et al. (2, 3) reexamined the H.J.B. kindred and provided evidence for two different defective apolipoprotein B (apoB) alleles: one yielding a truncated apoB, apoB37, and a second yielding very low amounts of a full-length apoB100. They demonstrated that the three family members with extremely low LDL cholesterol levels were compound heterozygotes, whereas subjects with moderately low cholesterol levels were heterozygous for either the apoB37 allele or the allele yielding low amounts of apoB100. Subsequent studies revealed that the mutant allele yielding apoB37 had a 4-base-pair (bp) deletion that resulted in a premature stop codon and a truncated apoB protein containing 1728 amino acids (4).The defect in the second mutant allele yielding very low levels of apoB100 is the subject of this report. The clue that led to the understanding of this allele was the recognition that H.J.B., as well as the other two compound heterozygotes, actually had four bona fide apoB species within their plasma lipoproteins: apoB37, apoB48, apoB100, and apoB86. In this study, we demonstrate that apoB86 and apoB100 are the products of a single mutant apoB allele, which we have designated the apoB86 allele. We show that the apoB86 allele has a 1-bp deletion in exon 26 of the apoB gene and that this frameshift mutation clearly results in the synthesis of apoB86. Furthermore, in cell culture expression studies, the apoB86 allele, which contains a premature stop codon, nevertheless results in the synthesis of a...