A defective gene associated with atherosclerosis: Tangier disease is caused by mutations in the ATP binding cassette transporter 1 (ABC1). S. Rust¹, M. Rosier², H. Funke¹, J. Real³, Z. Amoura⁴, J.-C. Piette⁴, J.-F. Deleuze², H.B. Brewer⁵, N. Duverger², P. Denéfle², G. Assmann¹. 1) Molecular Genetics, Inst. f. Arteriosclerosis Res., Muenster, NRW, Germany; 2) Core Genomics & Cardiovascular Departments, Rhône-Poulenc Rorer, 91006 Evry, France; 3) Universidad Departamento de Medicina, Hospital Clinico Universitario, Avda V Blasco Ibanez 17, 46010 Valencia, Spain; 4) Service de Médicine Interne, Hopital Pitié-Salpétrière, Paris, France; 5) National Institutes of Health, National Heart Lung and Blood Institute, Bethesda, Maryland, USA.

   Tangier disease was first discovered nearly 40 years ago by Donald Fredrickson and colleagues in two sibs living on Tangier Island in Chesapeake Bay, Virginia, USA. This is an autosomal codominant condition characterized in the homozygous state by the absence of HDL cholesterol from plasma, hepatosplenomegaly, peripheral neuropathy, and, frequently, premature coronary artery disease (CAD). In heterozygotes, HDL cholesterol levels are about half-normal. 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 Tangier families. We here report that we have refined our previous linkage of the Tangier disease gene to a 1 cM region between markers D9S271 and D9S1866 on chromosome 9q31 in which we found the human ATP cassette binding transporter 1 (ABC1) gene. Moreover, a change in ABC1 expression level upon cholesterol loading of phorbol ester-treated THP1 macrophages was found, substantiating ABC1s role in cholesterol efflux. The full length cDNA was cloned and the gene was sequenced in several unrelated families including the original case from Tangier Island. Six different gene disrupting mutations (deletions/insertions, stop codons) were discovered demonstrating that defects in ABC1, a member of the ABC transporter superfamily, are the cause of Tangier disease. The involvement of ABC transporters in cholesterol efflux may open new avenues for anti-atherosclerotic therapies.