Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(lys146—-gln) variant results in a dominant mode of inheritance

As determined by isoelectric focusing, most patients with familial dysbetalipoproteinemia (FD) exhibit the homozygous apolipoprotein (apo) E2E2 phenotype. Only rarely does FD develop in the more common heterozygous phenotypes E3E2 or E4E2. In fact, only 1 to 4% of the E2E2 homozygotes will develop FD. We wondered whether this reduced penetrance of FD in E2E2 homozygotes could be due to additional heterogeneity in the APOE*2 allele. In the literature a number of different mutations causing an E2 isoelectric focusing variant have been described. To study the genetic heterogeneity of the APOE gene, hybridization of enzymatically amplified genomic DNA with mutation-specific oligonucleotide probes was applied. All FD patients (n = 40) with the E2E2 phenotype appeared to be homozygous for the common E2(arg158—-cys) mutation. However, all three unrelated patients with the E3E2 phenotype exhibited the rare E2(lys146—-gln) mutation due to an A—-C substitution at nucleotide position 3,847 of the APOE gene. This mutation was not found among normolipidemic individuals with the E2E2 (n = 13) or E3E2 phenotype (n = 120) selected from a random population sample. Family studies of the three probands heterozygous for the E*2(lys146—-gln) allele showed that this rare allele predisposes to FD with high penetrance. We conclude that FD is a genetically heterogeneous disease entity, displaying a recessive mode of inheritance with strongly reduced penetrance in case of the common E2(arg158—-cys) variant and with a dominant mode of inheritance with high penetrance in case of the rare E2(lys146—-gln) mutant. It should be noted that in this dominant form presymptomatic diagnosis is possible.