Apolipoprotein E2 (Arg-136-->Cys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia

Abstract

Type III hyperlipoproteinaemia (HLP) is usually associated with homozygosity for apolipoprotein (apo) E2 (Arg‐158→Cys). We identified a 46‐year‐old white female with severe hyperlipidaemia and the heterozygous apo E3/2* phenotype. Typical clinical characteristics of type III HLP, i.e. palmar xanthomas (orange–yellowish discolorations of the palmar creases) and tuberoeruptive xanthomas, were present in the patient. Without therapy the patient's serum triglycerides (1.098 mg dL−1), cholesterol (546 mg dL–1), very low‐density lipoprotein (VLDL) cholesterol (372 mg dL−1) and the apo E concentration (25.0 mg dL−1) were distinctly elevated as well as her VLDL cholesterol to serum triglyceride (TG) ratio at 0.34 (normal ratio about 0.2). Direct sequencing of polymerase chain reaction (PCR)‐amplified segments of the apo ε gene identified a thymine for cytosine (C→T) exchange in the first base of codon 136 that is predictive for a Cys (T GC) for Arg (C GC) substitution in the encoded amino acid sequence. Two children, an 18‐year‐old female with the heterozygous apo E4/2* phenotype, a 25‐year‐old female with the heterozygous apo E3/2* phenotype and the 73‐year‐old father of the proband with the heterozygous apo E3/2* phenotype are also carriers of the rare mutant. The father has severe atherosclerosis and lipid values compatible with the diagnosis of type III HLP. The affected children have hyper/dyslipidaemia but as yet no clinical expression of the disease. We propose that in the analysed family this rare apo E2 (Arg‐136→Cys) variant is associated with late‐onset dominance of type III HLP.