Background: We found an unexplained, persistent discrepancy between the outcomes of two apolipoprotein-E (apo-E) genotyping methods for a patient with features of familial dysbetalipoproteinaemia (FD). Polymerase chain reaction - restriction fragment length polymorphism resulted in the apo-ε2/ε2 genotype, whereas minisequencing indicated apo-ε2/ε3. The discrepancy was predicted to derive from a novel mutation.
Methods: Sequencing of patient DNA, set-up of a mutation analysis method and establishment of mutation occurrence in 19 family members of the proband and investigation of its association with serum lipid indices.
Results: Sequencing demonstrated a G-insertion in codon 95 or 96 (95AAG-96-GAG-95AAG-96GGA-G) of the apo-ε3 allele. The mutation, designated apo-ε3Groningen, was predicted to cause a frameshift, a premature stop codon at codon 146 (AAGεTAA) and the expression of a truncated apo-E protein, if any. Four family members with the apo-ε3Groningen were identified. Two family members with apo-ε3/ε3Groningen had serum lipid indices within reference ranges but low-serum apo-E. Three subjects with apo-ε2/ε3Groningen, proband included, had serum cholesterol, triglycerides and calculated low-density lipoprotein-cholesterol levels above the reference ranges. Their electrophoresis pattern showed the classical broad-beta band, indicative of FD.
Conclusion: Apo-ε3Groningen heterozygosity is unlikely to precipitate FD, unless provoked by compound apo-ε2 heterozygosity or other FD precipitating factors.
