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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:1189-1196.)
© 1996 American Heart Association, Inc.

Articles

Homozygous Familial Hypobetalipoproteinemia

Increased LDL Catabolism in Hypobetalipoproteinemia Due to a Truncated Apolipoprotein B Species, Apo B-87_Padova

Carlo Gabelli; Claudio Bilato; Scipione Martini; Gregory E. Tennyson; Loren A. Zech; Alberto Corsini; Marco Albanese; H. Bryan Brewer, Jr; Gaetano Crepaldi; Giovannella Baggio

the Institute of Internal Medicine, University of Padua, Padova, Italy (C.G., C.B., S.M., M.A., G.C., G.B.), the Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (G.E.T., L.A.Z., H.B.B.), and the Institute of Pharmacological Sciences, University of Milan, Italy (A.C.).

Correspondence to Dr Carlo Gabelli, University of Padua, Institute of Internal Medicine, via Giustiniani 2, I-35128 Padova, Italy. E-mail athero@ipdunix.unipd.it.

Mutations on the apolipoprotein (apo) B gene that interfere with the full-length translation of the apoB molecule are associated with familial hypobetalipoproteinemia (FHBL), a disease characterized by the reduction 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 deletion 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 individuals 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 in one homozygous patient and two normal control subjects. ApoB-87 LDL showed a similar metabolism in all three subjects, with a fractional catabolic rate more than double that of normal LDL. The rate of entry of 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 particles to inhibit the uptake and degradation of normal apoB-100 LDL by normal human cultured fibroblasts. These results indicate that apoB-87 LDL has an enhanced ability to interact with the LDL receptor; the increased apoB catabolism contributes to the hypobetalipoproteinemia and may explain the mild expression of the disease in the two homozygous individuals.

Key Words: lipoproteins • apolipoprotein B • cholesterol metabolism • atherosclerosis

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