Type III hyperlipoproteinemia is characterized by delayed chylomicron and VLDL 
remnant catabolism and is associated with homozygosity for the apoE-2 allele. We 
have identified a kindred in which heterozygosity for an apoE mutant, apoE-1 
(Lys146-->Glu), is dominantly associated with the expression of type III 
hyperlipoproteinemia. DNA sequence analysis of the mutant apoE gene revealed a 
single-point mutation that resulted in the substitution of glutamic acid (GAG) 
for lysine (AAG) at residue 146 in the proposed receptor-binding domain of apoE. 
The pathophysiological effect of this mutation was investigated in vivo by 
kinetic studies in the patient and six normal subjects, and in vitro by binding 
studies of apoE-1 (Lys146-->Glu) to LDL receptors on human fibroblasts and to 
heparin. The kinetic studies revealed that apoE-1 (Lys146-->Glu) was catabolized 
significantly slower than apoE-3 in normals (P < 0.005). In the proband, the 
plasma residence times of both apoEs were substantially longer and the 
production rate of total apoE was about two times higher than in the control 
subjects. ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, 
and its ability to displace LDL in an in vitro assay was reduced to 7.7% 
compared with apoE-3. The affinity of apoE-1 (Lys146-->Glu) to heparin was also 
markedly reduced compared with both apoE-2 (Arg158-->Cys) and apoE-3. These 
abnormal in vitro binding characteristics and the altered in vivo metabolism of 
apoE-1 (Lys146-->Glu) are proposed to result in the functional dominance of this 
mutation in the affected kindred.