Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Apolipoprotein A-I Deficiency [E78.6]

OMIM numbers: 604091, 107680 (APOA1)

Dr. med. Hanns-Georg Klein

Scientific Background

Apolipoprotein A-I (apoA-I) is one of the central apoproteins involved in the metabolism of HDL particles. Primary apoA-I deficiency is a rare, autosomal recessive, inherited metabolic defect characterised by an extremely low serum concentration of HDL cholesterol (< 10 mg/dl) and apoA-I (< 20 mg/dl). The results of many epidemiological studies show that decreased HDL-C concentrations, especially in combination with elevated LDL-C (LDL/HDL ratio > 3.5), represent a risk for coronary heart disease. ApoA-I-deficient individuals usually have an elevated coronary risk due to the disrupted cholesterol efflux from peripheral cells. Also characteristic for apoA-I deficiency is the phenotypical manifestation of planar xanthomas and corneal opacities. In a few extremely rare cases, mutations in the APOA1 gene have been described (apoA-I Milano) that exhibit no increased vascular risk, despite moderately lowered serum HDL-C and apoA-I. In fact, these carriers even exhibit an extended life expectancy due to an accelerated HDL metabolism.

The APOA1 gene is located on chromosome 11q23 in the what is known as the apoprotein gene cluster which also includes the apoproteins C-III and A-IV. The transcription of these genes is partly controlled by common regulatory elements and, in very rare cases, a combined apoA-I, C-III and A-IV defect has been described. Mutations in the LCAT (LCAT deficiency, Fish Eye Disease) or ABCA1 gene (Tangier disease) may also be causal for HDL deficiency (hypoalphalipoproteinemia). The coronary risk is considered to be lower in LCAT deficiency and Tangier disease compared to apoA-I deficiency.