Published online 26 August 2010 | Nature | doi:10.1038/news.2010.434

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Diseased cells have harnessed a cancer-causing mechanism to banish a mutant gene.

The vanishingly rare skin disease ichthyosis with confetti (IWC) is characterised by healthy patches in a sea of inflamed skin. Science/AAAS

Cells that can get the better of a rare skin disorder have helped scientists to explain the disease. Curiously, some patients' cells can eliminate the disease-causing mutation that underlies ichthyosis, and as a result have healthy patches of skin speckled all over their bodies.

By analysing the DNA in these areas and in affected ones, scientists have pinpointed the gene responsible for the disease, as well as the cellular mechanism responsible for its patchy disappearance1.

Ichthyosis is characterized by a breakdown in the structure of skin cells that leaves patients with thick, scaly layers of inflamed skin. In one form, known as ichthyosis with confetti (IWC), patients develop small patches of healthy skin that grow in number and size over time.

Dermatologists at Yale University School of Medicine in New Haven, Connecticut, initially identified two patients with the condition — too few to find a disease-causing mutation using traditional approaches.

But when one of the researchers, Keith Choate, mentioned the healthy patches to Yale geneticist Richard Lifton, Lifton had an idea. "Just looking at it, we thought, well, gosh — the genetics of this disease is caused by a dominant mutation and these spots represent revertants," or cells that had lost the mutation, he says.

Likely explanation

Cells can undergo spontaneous mutations that 'fix' a disease-causing gene, but this process is too rare to have occurred in every healthy spot in patients with IWC. A likelier explanation, Lifton reasoned, was a process called mitotic recombination, whereby dividing maternal and paternal chromosomes exchange DNA. This process is linked to cancer because it can allow a once recessive cancer-causing mutation to suddenly take effect.

With this theory in mind, Lifton, Choate and their colleagues scoured the genomes of one patient's diseased and healthy skin cells, and blood, for signs of mitotic recombination. A 3-million-base-pair swathe of chromosome 17 fit the bill. It also contained a cache of keratin genes — reasonable candidates for a skin disease.

DNA sequencing identified a mutation in keratin 10 (KRT10) in diseased cells that was absent from healthy skin cells. Ordinarily, the keratin 10 protein forms filaments in the cytoplasm that maintain the integrity of skin cells. However, in the mutants, the protein was found mostly in the nucleus and the nucleolus, a cellular structure in which ribosomes are produced. Six other patients with IWC had similar mutations, the authors found.

They theorize that each healthy patch represents a single mitotic recombination in a skin stem cell that created a cell containing two healthy copies of KRT10. With the mutation gone, the stem cell cranks out healthy, differentiated skin cells that compete with diseased cells. "What we're seeing here is natural selection occurring under the skin," Choate says.

But natural selection may not be the only explanation for the hundreds of spots that IWC patients develop. Mitotic recombination is uncommon, so something could be spurring it on. One possibility, Lifton says, is that when keratin 10 builds up in the nucleus and nucleolus, it promotes mitotic recombination.

"It's interesting speculation," says Bert Vogelstein, a cancer researcher at Johns Hopkins University in Baltimore, Maryland. Alternatively, mitotic recombination is known to occur at varying frequencies along the genome, and KRT10 could be at a hot spot.

"It's a cool story, and a very nice piece of genetic detective work," says Scott Keeney, a molecular biologist at the Memorial Sloan-Kettering Cancer Center in New York. He also supports the idea that mitotic recombination occurs more often in patients with IWC. "I'm stumped about how that might work," he says.

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Despite this knowledge gap, Lifton's team is already thinking about harnessing the process to eliminate mutations that cause other diseases. Blood disorders would be a good place to start because recombined blood stem cells could be easily screened for cancer-causing mutations before being injected into patients.

"It's an interesting idea, but it's pretty far off in the future," Vogelstein says.

Meanwhile, it's not clear whether mitotic recombination will eventually cure IWC patients of all their scales. The oldest patient in the study is in his mid-forties, and he has more and larger healthy patches than the others. "He hasn't reverted his entire skin surface," Choate says, "but one could envision that he could certainly do this over the course of his lifetime."