Novel mutations in the gene encoding ATP-binding cassette 1 in four Tangier disease kindreds

Tangier disease (TD) is an autosomal co-dominant disorder in which homozygo tes have a marked deficiency of high density lipoprotein (HDL) cholesterol and, in some cases, peripheral neuropathy and premature coronary heart dise ase (CHD), Homozygotes are further characterized by cholesteryl ester depos ition in various tissues throughout the body, most notably in those of the reticuloendothelial system. Several studies have demonstrated that the exce ss lipid deposition iu TD is due to defective apolipoprotein-mediated efflu x of cellular cholesterol and phospholipids. Although much progress has bee n made in our understanding of the metabolic basis of TD, the precise molec ular defect had remained elusive until very recently, By positional cloning methods, we: 1) confirm the assignment of TD to chromosome 9q31, 2) provid e evidence that human ATP-binding cassette-1 (hABC-1) maps to a 250 kb regi on on 9q31, and 3) describe novel deletion, insertion, and missense mutatio ns in the gene encoding hABC-1 in four unrelated TD kindreds. These results establish a causal role for mutations in hABC-1 in TD and indicate that th is transporter has a critical function in the regulation of intracellular l ipid trafficking that dramatically affects plasma HDL cholesterol levels.