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

Tangier disease (TD) was first discovered nearly 40 years ago in two siblin gs living on Tangier Island(1). This autosomal co-dominant condition is cha racterized in the homozygous state by the absence of HDL-cholesterol (HDL-C ) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently pre mature coronary artery disease(1) (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals(1). 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 f amilies(2). We report here refining of our previous linkage of the TD gene( 3) 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 lo ading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced t he gene in two unrelated families with four TD homozygotes. In the first pe digree, a 1-bp deletion in exon 13, resulting in truncation of the predicte d protein to approximately one-fourth of its normal size, co-segregated wit h the disease phenotype. An in-frame insertion-deletion in exon 12 was foun d in the second family. Our findings indicate that defects in ABC1, encodin g a member of the ABC transporter superfamily, are the cause of TD.