The gene encoding ATP-binding cassette transporter 1 is mutated in Tangierdisease

Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism (1). It is characterized by absence of plasma high-density lipoprotein (HDL ) and deposition of cholesteryl esters in the reticulo-endothelial system w ith splenomegaly and enlargement of tonsils and lymph nodes(.)(2) Although low HDL cholesterol is associated with an increased risk for coronary arter y disease, this condition is not consistently found in TD pedigrees. Metabo lic studies in TD patients have revealed a rapid catabolism of HDL and its precursors(2). In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism(3,4). HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibrobl asts(5-7), which have a reduced in vitro growth rates. The TD locus has bee n mapped to chromosome 9q31 (ref. 9). Here we present evidence that TD is c aused by mutations in ABC1, encoding a member of the ATP-binding cassette ( ABC) transporter family, located on chromosome 9q22-31 (ref. 10), We have a nalysed five kindreds with TD and identified seven different mutations, inc luding three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the underst anding of cellular HDL metabolism and reverse cholesterol transport, and it s association with premature cardiovascular disease.