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A New Apolipoprotein B-100 Variant in a Family With Premature Atherosclerosis and Hyperapobetalipoproteinemia

John A. A. Ladias, MD; Peter O. Kwiterovich, Jr, MD; Hazel H. Smith; Michael Miller, MD; Paul S. Bachorik, PhD; Trudy Forte, PhD; Aldons J. Lusis, PhD; Stylianos E. Antonarakis, MD

JAMA. 1989;262(14):1980-1988.

Abstract
A 43-year-old woman with severe coronary artery disease and hyperapobetalipoproteinemia was heterozygous for an abnormal Msp I apolipoprotein B (APOB) gene fragment because of the absence of the Msp I site around codon 4046 in exon 29 of the APOB gene. Using the polymerase chain reaction technique, 134 base pairs containing the mutant Msp I site were amplified, cloned, and sequenced. The mutation was a C to T transition, substituting tryptophan for arginine at amino acid position 4019 of the mature ApoB-100 protein. Seven relatives of the proband had the same mutation, which has been called "ApoB-100 Hopkins." Only three of seven relatives with the mutation had hyperapobetalipoproteinemia; one was borderline while two other relatives without the mutation had hyperapobetalipoproteinemia. Mutant low-density lipoprotein (LDL) was bound and degraded to a greater extent than normal LDL in cultured human fibroblasts. In conclusion, a new mutation, ApoB-100 Hopkins, was not linked to the hyperapobetalipoproteinemia phenotype, which also was segregating in this family. The increased affinity of this mutant LDL for the LDL receptor may be due to a specific effect of ApoB-100 Hopkins or to altered LDL size and composition.

(JAMA. 1989;262:1980-1988)

Author Affiliations
From the Divisions of Genetics (Drs Ladias and Antonarakis) and Lipid Research Atherosclerosis (Drs Kwiterovich, Miller, and Bachorik and Ms Smith), the Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Md; the Department of Medicine, Microbiology and Molecular Biology Institute, University of California at Los Angeles (Dr Forte); and the Donner Laboratory, Berkeley, Calif (Dr Lusis).

Footnotes
Reprint requests to Department of Pediatrics, The Johns Hopkins Hospital, 600 N Wolfe St, CMSC 1004, Baltimore, MD 21205 (Dr Antonarakis).

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