Genetic insight from a rare skin disease

Geneticist Richard Lifton had been more focused on heart than skin disease, but when a former postdoc dermatologist returned to describe a baffling case, the head of Yale's genetics department was intrigued.

The patient's skin was a hodgepodge of red and white patches, said Lifton. The diagnosis was a rare genetic disease called "ichthyosis en confetti," named after the diseased skin's scaly look. The red patches were inflamed skin typical of the condition, but the white patches were a mystery to Lifton and his former postdoc.

Genetic sequencing revealed that those white patches were normal skin, free of the disease-causing genetic mutation. In essence, the disease had essentially expelled the bad genes through a process called mitotic recombination, when cells mis-shuffle their genetic material before dividing.

Normally, a cell divides into two identical daughter cells, each with a maternal and a paternal copy of each gene.

But occasionally an errant exchange between two chromosomes leads to one daughter cell with two maternal copies of a gene and another with two paternal copies.

In the past, that phenomenon was known to lead to cancer in patients. With no healthy "backup" copies, that cell would grow into a malignant tumor.

But in ichthyosis, the cell that got two copies of the bad gene died, while the one with two copies of the normal genes grew into a patch of healthy skin.

"You're curing a disease by losing a mutant copy," he said.

Lifton said he hopes they can learn to rev up this process in patients.

Scientists might also harness this process in other diseases caused by a single "dominant" mutant gene, he said. In some blood diseases, for example, they could extract bone marrow and comb it for isolated healthy cells that could be encouraged to grow and then be returned to the patient. - Faye Flam