Nature Genetics pp 336 - 345, pp 347 - 351, pp 352 - 355 and pp 316 - 318

Orange tonsils and the virtual absence of high-density lipoproteins (HDL) are striking features of Tangier disease (TD), first identified on Tangier Island in the middle of Chesapeake Bay, Virginia, USA. Scientists have searched intensively for the gene that causes this rare disorder because low levels of HDL are linked to coronary heart disease. The genetic defect underlying TD has now been discovered by three independent groups, led by Michael Hayden (of the University of British Columbia), Gerd Schmitz (of the University of Regensburg) and Gerd Assmann (of Westfalische Wilhelms-Universität Münster). The researchers determined that TD is caused by mutations in the gene ABC1, which encodes a protein needed for the transport of cholesterol out of cells.

Cells make cholesterol as well as absorbing it from the blood plasma. While cholesterol is needed for normal tissue function, an excessive build-up can lead to the formation of atherosclerotic plaques. To maintain the balance inside a cell, cholesterol is also transferred out of the cell and back into the plasma, where it is collected by HDL particles and transported to the liver. The cells of TD patients are unable to export cholesterol, leading to an accumulation of cholesterol in the tonsils and lymph glands, and in some cases, the arterial walls, where it can lead to severe arteriosclerosis. The discovery that mutations in ABC1 cause TD reveals that the protein encoded by ABC1 is needed for cholesterol efflux. The extremely low levels of HDL in TD patients also indicate that the export of cellular cholesterol, as mediated by ABC1, is required for making HDL. Apo AI lipoproteins form the core of HDL particles and they need to acquire lipid molecules from the membranes of cells to be transformed into HDL; otherwise, apo AI lipoproteins are removed from the plasma and HDL particles are never formed.

In an accompanying News & Views article, Stephen Young and Christopher Fielding (of the University of California) discuss the mechanisms by which ABC1 mediates cholesterol export and HDL formation. As ABC1 mutations cause inherited defects in HDL metabolism, it is possible that subtle variations in ABC1 are responsible for the reduced levels of HDL observed in patients suffering coronary heart disease. It is also feasible that coronary heart disease could be treated using pharmaceutical drugs that increase the expression of ABC1, resulting in increased levels of HDL and prevention of cholesterol accumulation in blood vessel walls.

Nature Genetics pp 327 - 335 and pp 319 - 320

An initial step that geneticists typically take to explore the function of a gene is to inactivate it in a model organism, such as mouse, worm, fly or yeast, to see the effects. While this approach often provides insight into the role of a given gene, it doesn't always work. Inactivation of a gene sometimes results in no difference between the mutant animal and a normal animal. This is because other genes can act as 'back-ups', compensating for the loss of function of the mutated gene. Nathaniel Heintz (of The Rockefeller University) and colleagues now demonstrate that increasing the number of copies (or 'dosage') of a gene is a powerful alternative strategy for investigating gene function.

The gene Zipro1, which encodes a protein that activates the expression of other genes, is expressed in granule neurons. (These account for approximately 80% of all neurons in the brain.) Heintz and coworkers found that inactivating the gene in mice has no apparent effect. But when they introduced additional copies of Zipro1 into mice, mice over-produced granule precursor cells during post-natal development, leading to enlargement of the cerebellum. In addition, the mice displayed excessive proliferation of skin cells and abnormal hair follicle development, and consequently hair loss (alopecia). These findings indicate that Zipro1 is critical to the final stages of brain development and for normal formation of hair follicles.

As highlighted by Susan Magdaleno and Tom Curran (of St Jude Children's Research Hospital) in an accompanying News & Views article, this report demonstrates that adding extra copies of a gene can provide new information about the function of a gene that would not be revealed by the traditional experimental strategy of gene inactivation.

Nature Genetics pp 356 - 400

The skin acts as a barrier between the body and the environment, preventing dehydration and protecting against microbial infection. The skin regenerates unceasingly, with new epidermal cells emerging from an underlying proliferative layer and then moving through several upper layers before reaching the skin surface. As it nears the surface, each skin cell starts to make a specialized protein 'sac' called the cornified envelope. This acts like a 'cast' of the cell and serves as a scaffold on which fat molecules, called lipids, assemble to form a sealed barrier. The skin acquires the ability to form this protective barrier shortly before birth.

Elaine Fuchs and colleagues (of the University of Chicago) have now identified a critical factor, Klf4, required for the barrier function of the skin. Klf4 is a transcription factor, which binds to specific target genes and turns their expression on or off. The researchers generated mice deficient in Klf4 and found that they die shortly after birth due to rapid dehydration. Not only can the mice not prevent fluid escaping the skin, they also can't stop other substances penetrating it: when immersed in a blue dye solution, the Klf4-deficient newborn pups turn blue whereas normal mice have a skin barrier that is impenetrable to the dye. Closer inspection of Klf4-deficient skin reveals that the lower layers of the epidermis are intact but the upper layers are abnormal. The normally smooth, plump cornified envelope looks rough and crumpled in Klf4-deficient mice. This report indicates that Klf4 is needed to make a cornified envelope and assemble lipids on this scaffold. This study provides the first clues to the molecular pathways that create the impenetrable barrier of the skin.