Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1

Abstract

Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island. This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals. Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families. We report here refining of our previous linkage of the TD gene to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1). We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes. In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype. An in-frame insertion-deletion in exon 12 was found in the second family. Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD.

ABCA1 upregulating apolipoproein M expression mediates via the RXR/LXR pathway in HepG2 cells

“…Mutations in the ABCA1 gene result in the Tangier disease (TD) [17,18]. ABCA1 promotes efflux of phospholipids and cholesterol to the lipid-poor apoAI in a process that involves the direct binding of apoAI to the transporter [19].…”

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

“…Since the discovery that mutations in ABCA1 are the primary cause of Tangier disease (Brooks-Wilson et al 1999;Bodzioch et al 1999;Rust et al 1999), in which HDL-cholesterol (HDL-C) levels are extremely low, several hundred articles have appeared describing the function of the protein, as well as attempts to associate common polymorphism in ABCA1 to cholesterol-related traits. The ABCA1 protein mediates the unidirectional efflux of free cholesterol and phospholipids from cells, facilitating the lipidation of most of the exchangeable apolipoproteins (including APOA1 and APOE) and the formation of nascent HDL molecules (Yancey et al 2003).…”

Role of nutrient transporters in lifestyle-related diseases

“…The ATP-binding cassette (ABC) transporter A1 (ABCA1) has been identified as a causative gene for Tangier disease, in which patients exhibit low levels of serum HDL, hypercholesterolemia, and a high risk of cardiovascular disease [28][29][30] . ABCA1 is widely expressed in various tissues, and mainly transfers cholesterol from peripheral tissue to pre-HDL, known as reverse cholesterol transport 31,32) .…”