Abstract 16714: The “Apolipoprotein EBethesda” Variant is a Digenic Phenotype of APOE p.R176C/GALNT2 p.D314A
Introduction: Apolipoprotein E (apoE) is a key protein in lipoprotein metabolism that protects against atherosclerosis. In 1982, a novel apoE protein isoform in a Type III hyperlipidemia patient was described by Brewer and colleagues at NIH. The proband had total cholesterol (TC) and triglyceride (TG) levels up to 550 and 900 mg/dL, respectively, and xanthomas that resolved with treatment. The VLDL-cholesterol to TG ratio, however, remained greater than 0.3. This Type III hyperlipidemia phenotype is generally associated with APOE c.526C>T;p.R176C (“apoE2”) homozygosity, but isoelectric focusing suggested the patient was a compound heterozygote for apoE2 and a new apoE isoform, “Apolipoprotein EBethesda” (apoEBethesda, also known as “apolipoprotein E Bethesda”). These findings suggested that apoEBethesda may be coded by a new APOE allele. However, sequencing data showed the patient was only heterozygous for apoE2 and no novel “apoEBethesda” mutation was ever found. The proband’s son, also a Type III hyperlipidemic patient with both the apoE2 and apoEBethesda isoforms, continued to be followed at NIH.
Hypothesis & Methods: We hypothesized that exome sequencing of the proband’s son would identify the molecular defect in the “ApoEBethesda” isoform. Exome sequencing using Illumina TruSeq capture and HiSeq sequencing with standard chemistry was employed.
Results: Relevant clinical data (on statins, niacin, and natural lipid supplements) were: apoA-I, 174; apoB, 78; TC, 190; TG, 124; HDL-C, 66; LDL-C, 102; BNP, 156; CT- Calcium, 1108. Off medications, TC and TG were 323 and 2030 mg/dL, respectively. The patient was confirmed to be heterozygous for APOE2 but again, no novel “apoEBethesda” mutations were found. He was, however, heterozygous for GALNT2 c.941A>C;p.D314A. GALNT2 is a key enzyme in O-glycosylation.
Conclusion: We suggest that the “apoEBethesda” phenotype is actually the consequence of digenic mutations for APOE c.526C>T;p.R176C (APOE2) , coupled with a mutation in GALNT2, which causes defective glycosylation of APOE. GALNT2 is known to glycosylate apoC-III and our hypothesis is that APOE or APOE2 is also a substrate for this enzyme. Functional studies are underway to address this hypothesis.
Author Disclosures: L.A. Freeman: None. R.D. Shamburek: None. L. Biesecker: None. A.T. Remaley: None.
- © 2016 by American Heart Association, Inc.