Genetic variants of ApoE account for variability of plasma low-density lipoprotein and apolipoprotein B levels in FHBL.
We report two novel APOB mutations causing short apolipoprotein B (apoB) truncations undetectable in plasma and familial hypobetalipoproteinemia (FHBL). In Family 56, a 5 bp deletion in APOB exon 7 (870_874del5) causes a frame shift, converting tyrosine to a stop codon (Y220X) and producing an apoB-5 truncation. In Family 59, a point mutation (1941G>T) in APOB exon 13 converts glutamic acid to stop codon (E578X), specifying apoB-13. A recurrent mutation in exon 26 (4432delT) produces apoB-30.9 in Family 58. In some members of these families, we observed that plasma low-density lipoprotein (LDL) cholesterol and apoB levels were unusually low even for subjects heterozygous for FHBL. To ascertain whether genetic variations in apolipoprotein E (apoE) would explain some of the variations of apoB and LDL cholesterol levels, apoE genotypes were assessed in affected subjects from a total of eight FHBL families with short apoB truncations. Heterozygous FHBL with the epsilon3/epsilon4 genotype had 10-1 5mg/dL higher plasma LDL cholesterol and apoB levels compared to subjects with the epsilon2/epsilon3 and epsilon3/epsilon3 genotypes. The apoE genotype has been reported to account for approximately 10% of the variation of LDL cholesterol in the general population. It accounted for 15-60% of the variability of plasma LDL cholesterol or apoB levels in our FHBL subjects. The physiologic bases for the greater effects of apoE in FHBL remain to be determined.
Yue
Pin
P
Division of Endocrinology, Metabolism, and Lipid Research, Washington University, School of Medicine, St. Louis, MO 63110, USA.
Isley
William L
WL
Harris
William S
WS
Rosipal
Stefan
S
Akin
Carl D
CD
Schonfeld
Gustav
G
D000328:Adult; D001055:Apolipoproteins B / Q000097:blood*; D001057:Apolipoproteins E / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D014644:Genetic Variation; D005838:Genotype; D018698:Glutamic Acid; D006147:Guanine; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000097:blood* / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D013941:Thymine; D014443:Tyrosine
D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D018698:Glutamic Acid; D014443:Tyrosine; D006147:Guanine; D013941:Thymine