HOMOZYGOUS FAMILIAL HYPOBETALIPOPROTEINEMIA - INCREASED LDL CATABOLISM IN HYPOBETALIPOPROTEINEMIA DUE TO A TRUNCATED APOLIPOPROTEIN-B SPECIES, APO B-87(PADOVA)

Mutations on the apolipoprotein (apo) B gene that interfere with the f ull-length translation of the apoB molecule are associated with famili al hypobetalipoproteinemia (FHBL), a disease characterized by the redu ction of plasma apoB and LDL cholesterol. In this report, we describe an FHBL kindred carrying a unique truncated apoB form, apoB-87(Padova) . Sequence analysis of amplified genomic DNA identified a single G del etion at nucleotide 12 032, which shifts the translation reading frame and causes a termination at amino acid 3978. Two homozygous subjects and seven heterozygous relatives were studied. Although homozygous ind ividuals had only trace amounts of LDL, they were virtually free from the symptoms typical of homozygous FHBL subjects. We investigated the in vivo turnover of radiolabeled normal apoB-100 LDL and apoB-87 LDL i n one homozygous patient and two normal control subjects. ApoB-87 LDL showed a similar metabolism in all three subjects, with a fractional c atabolic rate more than double that of normal LDL. The rate of entry o f apoB-87 in the LDL compartment was also markedly decreased compared with normal apoB-100. The increased in vivo catabolism of apoB-87 LDL was paralleled in vitro by a 2.5-fold increased ability of these parti cles to inhibit the uptake and degradation of normal apoB-100 LDL by n ormal human cultured fibroblasts. These results indicate that apoB-87 LDL has an enhanced ability to interact with the LDL receptor; the inc reased apoB catabolism contributes to the hypobetalipoproteinemia and may explain the mild expression of the disease in the two homozygous i ndividuals.