A 10-BP DELETION IN THE APOLIPOPROTEIN-EPSILON GENE CAUSING APOLIPOPROTEIN-E DEFICIENCY AND SEVERE TYPE-III HYPERLIPOPROTEINEMIA

Type III hyperlipoproteinemia (HLP) is usually associated with homozyg osity for apolipoprotein (ape) E2. We identified a 30-year-old male Ge rman of Hungarian ancestry with severe type III HLP and apo E deficien cy. The disease was expressed in an extreme phenotype with multiple cu taneous xanthomas. Apo E was detectable only in trace amounts in plasm a but not in the different lipoprotein fractions. Direct sequencing of PCR-amplified segments of the apo epsilon gene identified a 10-bp del etion in exon 4 (bp 4037-4046 coding for amino acids 209-212 of the ma ture protein). The mutation is predictive for a reading frameshift int roducing a premature stop codon (TGA) at amino acid 229. By western bl ot analysis, we found small amounts of a truncated apo E in the patien t's plasma. Family analysis revealed that the proband was homozygous - and 10 of 24 relatives were heterozygous - for the mutation. Heterozy gotes had, as compared to unaffected family members, significantly hig her triglycerides (TG), very low-density lipoprotein (VLDL) cholestero l and a significantly higher VLDL cholesterol-to-serum TG ratio, which is indicative of a delayed remnant catabolism. We propose that the ab sence of a functionally active apo E is the cause of the severe type I II HLP in the patient and that the mutation, even in a single dose in heterozygotes, predisposes in variable severity to the phenotypic expr ession of the disease.