Yale team finds a genetic rarity: A mutation that restores health

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Yale team finds a genetic rarity: A mutation that restores health

http://www.eurekalert.org/pub_releases/2010-08/yu-ytf082410.php

Errors in the copying of genes during cell division can cause numerous diseases,

including cancer. Yale School of Medicine scientists, however, have unraveled

the secrets of a much more rare phenomenon with potential therapeutic

implications – disease-causing genes that show a high frequency of self-repair.

In the August 26 issue of Science Express, the Yale team describes how one

mutated copy of a gene called keratin 10 causes a severe skin disease known as

ichthyosis with confetti. However, amidst the diseased skin, these patients also

have hundreds to thousands of spots of normal skin. This phenomenon, the

researchers report, occurs by the recombination of chromosomes prior to cell

division. Instead of producing one normal copy of the gene and one dominant,

disease-causing mutation, the exchange between chromosomes results in cells with

either two mutant copies or no mutant copies. If the latter occurs, spots of

normal, disease-free skin will form. The investigators used these recombination

events in spots of normal skin to map and ultimately identify the disease gene.

" Usually, you have a disease-causing mutation, and you are stuck with it, " said

Choate, assistant professor of dermatology and first author of the paper.

" But we demonstrate that in this disease, there is an unusually high frequency

of the appearance of mutation-free clones of cells. " The reason these particular

mutations revert to normal so frequently is not clear, note the scientists.

However, in all affected patients the normal tail end of the keratin 10 protein

is replaced by a protein sequence enriched for one amino acid, arginine. This

causes the mutant keratin 10 to end up in the wrong part of the cell. " We

believe the mis-localization of keratin 10 contributes both to the severity of

the disease and the appearance of the clones of normal skin, " said

Lifton, senior author of the paper and Sterling Professor and chair of the

department of genetics.

The researchers say that knowing that these particular mutations can revert with

high frequency gives them hope that they might find a way to mimic this process

to develop treatments for other genetic diseases.

" Perhaps rather than directly correcting disease-causing mutations we might be

able to recombine them away, similar to what happens in this disease, " said

Leonard Milstone, emeritus professor of dermatology and member of the research

team.

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Researchers at the University of California, San Francisco, Children's Mercy

Hospitals and Clinics and Texas Children's Hospital contributed to the study.

Other Yale authors on the paper are Yin Lu, Jing Zhou, Murim Choi, Anita Farhi

and Carol -,

The work was funded by the NIH and the Howa