Apo A-I is a crucial apoprotein involved in HDL metabolism. Primary Apo A-I deficiency is a rare autosomal recessive inherited metabolic defect characterized by extremely low serum concentrations of HDL cholesterol (< 10 mg/dl) and Apo A-I (< 20 mg/dl). Multiple epidemiological studies have shown that lowered HDL-C concentrations, especially in combination with elevated LDL cholesterol (LDL/HDL ratio >3.5), pose a risk for coronary heart disease. Apo A-I-deficient individuals generally have an increased coronary risk, caused by impaired efflux of cholesterol from peripheral cells. Variable phenotypic expression of planar xanthomas and corneal opacities are also characteristic of apo A-I deficiency. In addition, pathogenic variants in the APOA1 gene (e.g., Apo A-I-Milano) have been described in some very rare cases. Despite moderately decreased HDL-C and Apo A-I in serum, these variants do not seem to cause an increased vascular risk but may even lead to a longer life expectancy due to accelerated HDL metabolism.
The APOA1 gene is located on chromosome 11q23 in the so-called apoprotein gene cluster, which also includes apoproteins C-III and A-IV. Transcription of these genes is partially regulated by common regulatory elements. In rare cases, combined defects of Apo A-I, C-III and A-IV have been described. In addition to Apo A-I deficiency, variants in the LCAT (LCAT deficiency, Fish Eye Disease) or ABCA1 (Tangier Disease) genes may be causative for HDL deficiency (hypoalphalipoproteinemia). The coronary risk is lower in LCAT deficiency and Tangier disease as compared to Apo A-I deficiency.
Geller et al. 2018, J Lipid Res. 59:2421 / Dron et al. 2017, J Lipid Res. 58:2162 / Lee et al. 2013, J Clin Lipidol 7:169 / Schaefer et al. 2010, Curr Opin Lipidol 21:289 / Tall et al., in Scriver et al. 2001: The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Chapter 121