Gene Linked to Faulty Cholesterol Transport

Scientists have identified the gene for Tangier disease, in which a rare hereditary defect alters how the body handles cholesterol. The discovery, reported in the August issue of Nature Genetics, raises the possibility of developing drugs that protect against heart disease by raising blood levels of high-density lipoprotein (HDL)--a feat no one has yet accomplished.

The search for the Tangier culprit was a sprint to the finish after a very long marathon. Although the disease was discovered in 1961, it was not until 1998 that Gerd Assmann of the Westlischen Wilhelms University in Münster, Germany, and his colleagues identified a region of chromosome 9 as the location of the Tangier disease gene. But that still left the major job of finding the gene itself.

Enter Michael Hayden of the University of British Columbia in Vancouver. His group pinned down the approximate location of the gene by looking to see which chromosome 9 "markers" were consistently found in Tangier patients, but not in unaffected family members--an indication that the gene and marker lie close to one another. Meanwhile, Gerd Schmitz's group at the University of Regensburg in Germany looked for genes that were expressed differently in the cholesterol-laden cells of Tangier patients than in normal cells. This search also fingered the ABC1 gene as the most likely candidate--an ID confirmed when the gene turned up mutated in all five Tangier patients that the Schmitz team studied. Assmann's group found ABC1 through a combination of techniques.

The findings indicate that ABC1 normally moves cholesterol out of the cells. For example, Schmitz found that cells engineered to make extremely high amounts of ABC1 were so depleted of cholesterol that they died, while cells in which ABC1 synthesis was inhibited accumulated more, much as cells from Tangier patients do.

The discovery raises the possibility of developing drugs that protect against heart attack by targeting ABC1 and thus increasing HDL cholesterol levels in the blood, says cardiologist Dennis Sprecher of the Cleveland Clinic in Ohio. "This should open the doors to a general research effort into what regulates cholesterol coming out of cells," adds Christopher Fielding of the Cardiovascular Research Institute at the University of California, San Francisco. "There may be other mechanisms, but this is the first one, and it is a good place to start."