HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature

A 61-year-old white man of European ancestry with significant coronary heart disease since age 42 years and marked high-density lipoprotein (HDL) deficiency (HDL cholesterol 1 mg/dL) was evaluated. His fasting low-density lipoprotein cholesterol level was 42 mg/dL, and his triglycerides were 417 mg/dL on therapy with rosuvastatin 40 mg/day, ezetimibe 10 mg/day, fenofibrate 145 mg/day, and extended-release niacin 2 g/day. Further analysis of his plasma revealed an apolipoprotein (apo) A-I level of 23.5 mg/dL (approximately 20% of normal), and the absence of small alpha-4 HDL, medium alpha-3 HDL, and very large alpha-1 HDL, with only very small pre-beta-1 HDL and large alpha-2 HDL being present. APOA-I gene sequencing revealed a novel heterozygous in-frame insertion mutation with duplication of nucleotides 1535 through 1552 inserted at position 1553, causing a new amino acid glycine at codon 157 and a duplication of amino acids alanine, arginine, alanine, histidine, and leucine at codons 158-162. This novel apoA-I mutation results in the formation of apoA-I that appears to have abnormal lipid binding properties, resulting in impaired reverse cholesterol transport, probable enhanced clearance, and premature coronary heart disease.