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 Island¹. 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 disease¹ (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals¹. 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 families². We report here refining of our previous linkage of the TD gene³ 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.