Recently a paper in Science caught my attention since its title combines the words mitotic recombination with patients and Ichthyosis. Having worked with Drosophila during my PhD and now being in a vertebrate lab, I’m well aware of the existence of tools to induce mitotic recombination to generate somatic clones of mutant cells in certain tissues. So I had a closer look at the paper to understand more about the spontaneous occurrence of mitotic recombination in humans.
“Ichthyosis with confetti” (that’s what it’s called!), or IWC for short, is a very rare sporadic skin disease. Patients display red skin because their skin barrier is defective and they often die of bacterial infections. The reason the disease carries the word confetti in its name is that in the first year of life, the otherwise reddish body starts to be covered in pale spots, resembling confetti, which increase in number and size with age.
Now it has been found that these pale spots are clones of “revertant” cells arising through mitotic recombination. Most cells in the body of IWC patients are heterozygous for a spontaneous dominant mutation in the keratin 10 (KRT10) gene that causes the red skin disease phenotype. The exact mutation in KRT10 differs between patients, but all of the mutations result in frameshifts in the same alternative reading frame of KRT10. The product of this is an arginine-rich peptide that mis-localizes to the nucleolus and thereby disrupts the keratin filament network of skin cells. The pale clones of revertant cells are formed when mitotic recombination causes loss of heterozygosity in KRT10, so that these clones no longer carry the mutation and therefore behave like normal cells. Reversion to wild type occurs at very high frequency, suggesting a general increase in the rate of mitotic recombination in these individuals. It is not yet known what causes this elevation.
So, what did I learn from this? Mitotic recombination in multicellular organisms is not just a peculiarity that can be useful for experiments in model systems, it also occurs naturally in humans. For reasons still unknown, its rate can be increased when beneficial for the cells affected. Cancer cells appear to exploit this phenomenon, increasing the rate of mitotic recombination to speed loss of heterozygosity of tumor suppressor mutations to promote their survival and growth.
Who knows, one day induction of mitotic recombination to remove undesired mutations might even be used as a therapy in humans, as long as the homozygous mutant sister cells eliminate themselves as seems to be the case in IWC. As always, the frightening part in this scenario is the possibility of losing control and causing unwanted and potentially harmful mutations. We’ll see.
Choate KA, Lu Y, Zhou J, Choi M, Elias PM, Farhi A, Nelson-Williams C, Crumrine D, Williams ML, Nopper AJ, Bree A, Milstone LM, & Lifton RP (2010). Mitotic Recombination in Patients with Ichthyosis Causes Reversion of Dominant Mutations in KRT10. Science (New York, N.Y.) PMID: 20798280