Known mutations of apoB account for only a small minority of hypobetalipoproteinemia

Low LDL cholesterol and apoB levels in plasma cosegregate with mutations of apoB in some kindreds with familial hypobetalipoproteinemia. Approximately 35 apoB mutations, many specifying apoB truncations, have been described, Based on the centile nomenclature where the full-length nature apoB consist ing of 4536 amino acids is designated as apoB-100, only those truncations o f apoB >25% of normal length are detectable in plasma. Previously, we repor ted on five unrelated kindreds with familial hypobetalipoproteinemia in who m although no apoB truncations were detectable in plasma, lo iv apoB levels were nevertheless linked to the apoB gene, In one of those kindreds, we re ported a donor splice site mutation in intron 5 (specifying apoB-4). We no iv describe a nonsense mutation in exon 10 (apoB-9) in two of the other unr elated families, Both the apoB-4 and apoB-9 mutations have been reported by others in unrelated families. Recurrent mutations of apoB-40 and apoB-55 a lso have been reported, suggesting that recurrent mutations of apoB may acc ount for an appreciable proportion of familial hypobetalipoproteinemia kind reds, To test this hypothesis, we searched for four apoB mutations whose pr oducts are not detected in plasma including the apoB-4, apoB-9, and two oth er previously reported mutations in exons 21 and 25, We studied three group s with plasma cholesterols <130 mg/dl in whom no apoB truncations were dete cted iu plasma: a) 28 FHBL probands from St. Louis, b) 151 individual St. L ouisians, and c) 28 individual Sicilians. One subject from the 28 kindreds and two subjects among 151 hypobeta individuals from St, Louis harbored the exon 10 mutation, None of the other mutations were detected, Thus, among h ypobeta lipoproteinemic subjects without any detectable apoB truncations in plasma, <5% had an apoB truncation-producing mutation. As only about 0.5% of hypobeta lipoproteinemic subjects have plasma-detectable apoB truncation s, our data suggest that the known apoB truncations account for only a smal l proportion of hypo cholesterolemia.