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 homozygosity for apolipoprotein (apo) E2. We identified a 30-year-old male German of Hungarian ancestry with severe type III HLP and apo E deficiency. The disease was expressed in an extreme phenotype with multiple cutaneous xanthomas. Apo E was detectable only in trace amounts in plasma but not in the different lipoprotein fractions. Direct sequencing of PCR-amplified segments of the apo epsilon gene identified a 10-bp deletion in exon 4 (bp 4037-4046 coding for amino acids 209-212 of the mature protein). The mutation is predictive for a reading frameshift introducing a premature stop codon (TGA) at amino acid 229. By western blot analysis, we found small amounts of a truncated apo E in the patient's plasma. Family analysis revealed that the proband was homozygous--and 10 of 24 relatives were heterozygous--for the mutation. Heterozygotes had, as compared to unaffected family members, significantly higher triglycerides (TG), very low-density lipoprotein (VLDL) cholesterol and a significantly higher VLDL cholesterol-to-serum TG ratio, which is indicative of a delayed remnant catabolism. We propose that the absence of a functionally active apo E is the cause of the severe type III HLP in the patient and that the mutation, even in a single dose in heterozygotes, predisposes in variable severity to the phenotypic expression of the disease.
Feussner
G
G
Medizinische Universitätsklinik Heidelberg, Germany.
Dobmeyer
J
J
Gröne
H J
HJ
Lohmer
S
S
Wohlfeil
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001057:Apolipoproteins E / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D006951:Hyperlipoproteinemias / Q000235:genetics* / Q000378:metabolism; D008074:Lipoproteins / Q000032:analysis / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017421:Sequence Analysis; D017384:Sequence Deletion / Q000235:genetics; D014973:Xanthomatosis / Q000235:genetics
D001057:Apolipoproteins E; D017931:DNA Primers; D008074:Lipoproteins; D002784:Cholesterol