A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production

We report a novel apolipoprotein (apo) A-I truncation (apoA-IMytilene) due to a heterozygous nonsense mutation (c.718C > T, p.Gln216*) in a 68-year-old male proband with premature coronary heart disease (CHD), corneal arcus, and very low plasma concentrations of HDL cholesterol (HDL-C) and apoA-I. Two family members also had the same mutation. Our objectives were to characterize the kindred and to examine the kinetics of apoA-I, as well as cellular cholesterol efflux capacity in the proband.

We carried out the kinetic studies using a primed constant infusion of [5,5,5-D3]L-leucine and isotopic enrichment was determined by gas chromatography mass spectrometry in the proband and seven controls with low HDL-C. To assess cellular cholesterol efflux capacity, we used a validated ex vivo system that involved incubation of J774 macrophages with apoB-depleted serum from the proband, five controls with normal HDL-C, and two controls with low HDL-C.

Stable isotope kinetic studies indicated that the proband had an apoA-I production rate (PR) that was 41% lower than the mean PR observed in low HDL-C controls (n = 7). The cellular cholesterol efflux capacity assessment showed normalized cholesterol efflux capacity in the proband was decreased by 36% compared to the mean normalized cholesterol efflux capacity of normal controls (n = 5).

Our data indicate that this novel heterozygous apoA-I truncation is associated with markedly decreased levels of HDL-C, plasma apoA-I, and apoA-I in large α-1 HDL particles, as well as decreased total cellular cholesterol efflux and decreased apoA-I production.