Nature Genetics
22, 352 - 355 (1999)
doi:10.1038/11921
Tangier disease is caused by mutations in the gene encoding ATP-binding
cassette transporter 1Stephan Rust1, Marie Rosier2, Harald Funke1, 3, José Real4, Zahir Amoura5, Jean-Charles Piette5, Jean-Francois Deleuze2, H. Bryan Brewer6, Nicolas Duverger2, Patrice Denèfle2
& Gerd Assmann1, 31
Institut für Arterioskleroseforschung an der Westfälischen
Wilhelms-Universität Münster, Domagkstra e 3
, D-48149 Münster, Germany.
2
Core Genomics/Biotechnology and Cardiovascular Departments,
Rhône-Poulenc Rorer, 91006 Evry, France
. 3
Institut für Klinische Chemie und Laboratoriumsmedizin,
Westfälische Wilhelms-Universität, Albert-Schweitzer-Strae
33, D-48149 Münster, Germany.
4
Universidad Departamento de Medicina, Hospital Clinico
Universitario, Avda V Blasco Ibanez 17, 46010
Valencia, Spain. 5
Service de Médicine Interne, Hopital Pitié-Salpétrière
, Paris, France. 6
National Institutes of Health, National Heart Lung
and Blood Institute, Bethesda, Maryland, USA
.
Correspondence should be addressed to Stephan Rust Rusts@uni-muenster.deTangier 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.
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