Dysbetalipoproteinemia in a kindred with hypobetalipoproteinemia due to mutations in the genes for ApoB (ApoB-70.5) and ApoE (ApoE2).
We identified the first insertion mutation that specifies an apolipoprotein (apo)B truncation, apoB-70.5, in a father and son with hypobetalipoproteinemia (total and low-density lipoprotein [LDL] cholesterol < 5th percentile, plasma apoB levels approximately one third of normal). The mutation is due to insertion of an adenine (A) into a 7-A repeat between cDNA position 9754 and 9760 of the apoB gene, resulting in a frame shift of 13 new amino acids and a termination codon at amino acid residue 3197. The DNA mutation cosegregated with the apoB truncation and hypobetalipoproteinemia in the kindred. The two apoB-70.5/apoB-100 heterozygotes also are apoE2 homozygotes by genotyping; beta-very-low-density lipoprotein (VLDL) was present, and VLDL cholesterol/triglyceride ratios were increased (0.29) in the plasmas of both. Density gradient ultracentrifugation and gel filtration chromatography profiles showed increased amounts of particles in the VLDL and intermediate-density lipoprotein density and size ranges and relatively smaller peaks of LDL than in controls. Two populations of LDL were present, ApoB-70.5 was primarily associated with LDL particles of higher density and of smaller size than the LDL particles containing apoB-100. ApoB-48-containing particles were present in the VLDL of fasting plasmas of both subjects, and the postprandial levels of chylomicrons and remnants as measured by the vitamin A fat tolerance test were increased. In conclusion, both subjects heterozygous for apoB-70.5 and homozygous for apoE2 showed the classic characteristics of dysbetalipoproteinemia superimposed onto the hypolipoproteinemia state.
Groenewegen
W A
WA
University Utrecht, The Netherlands.
Krul
E S
ES
Averna
M R
MR
Pulai
J
J
Schonfeld
G
G
D000328:Adult; D000368:Aged; D001055:Apolipoproteins B / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D001483:Base Sequence; D005260:Female; D005796:Genes; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000235:genetics*; D006995:Hypobetalipoproteinemias / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation
D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008055:Lipids; D015335:Molecular Probes