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Rehovot scientists move to defuse Huntington's time bomb
Huntington's disease is a genetic time bomb: This horrific disorder appears at a predictable age in adulthood, causing a progressive decline in mental and neurological function, and finally death. So far, there is no cure for Huntington's or a number of similar ailments collectively known as trinucleotide repeat diseases. They are caused by an unusual genetic mutation: A three-letter piece of genetic code is repeated over and over in one gene. Scientists at the Weizmann Institute in Rehovot have now proposed a mechanism that provides an explanation for the remarkable precision of the time bomb. This explanation may point researchers in the direction of a possible prevention or cure.
The number of repeats in Huntington's patients ranges between 40 to over 70. Scientists have noted that, like clockwork, one can predict - by how many times the sequence repeats in a patient's gene - both the age at which the disease will appear and how quickly it will progress. The basic assumption has been that the protein fragment containing the amino acid (glutamine) encoded in the repeating triplet slowly builds up in the cells until it reaches toxic levels. This theory, unfortunately, fails to explain some of the clinical data. For instance, it doesn't explain why patients with two copies of the Huntington's gene don't exhibit symptoms earlier than those with a single copy. Plus, glutamine is produced in only some trinucleotide diseases, whereas the correlation between sequence length and onset age follows the same general curve in all of them, implying a common mechanism not tied to glutamine.
Research student Shai Kaplan in Prof. Ehud Shapiro's lab in the institute's biological chemistry department and the computer sciences and applied mathematics department realized the answer might lie in somatic mutations - changes in the number of DNA repeats that build up in our cells. The longer the sequence, the greater the chance of additional mutation, and the scientists realized that the genes carrying the disease code might be accumulating more and more DNA repeats, until some critical threshold is crossed.
Based on the literature on some 20 known trinucleotide repeat diseases and their knowledge of the mechanisms governing somatic mutation, Shapiro, Kaplan (also in the molecular cell biology department), and Dr. Shalev Itzkovitz created a computer simulation that could take a given number of genetic repeats and show both the age of onset and the way in which the disease would progress. Their findings were recently presented in PLoS Computational Biology.
The new disease model appears to fit all the facts and to provide a good explanation for the onset and progression of all the known trinucleotide repeat diseases. Lab experiments could test this model, say the scientists and, as it predicts that all these diseases operate by somatic expansion of a trinucleotide repeat, it also suggests that a cure for all might be found in a drug or treatment that slows the expansion process.
Source: Judy Siegel-Itzkovich. Weizmann scientists move to defuse Huntington's time bomb. JPost.com (15 December 2007) [FullText]
The number of repeats in Huntington's patients ranges between 40 to over 70. Scientists have noted that, like clockwork, one can predict - by how many times the sequence repeats in a patient's gene - both the age at which the disease will appear and how quickly it will progress. The basic assumption has been that the protein fragment containing the amino acid (glutamine) encoded in the repeating triplet slowly builds up in the cells until it reaches toxic levels. This theory, unfortunately, fails to explain some of the clinical data. For instance, it doesn't explain why patients with two copies of the Huntington's gene don't exhibit symptoms earlier than those with a single copy. Plus, glutamine is produced in only some trinucleotide diseases, whereas the correlation between sequence length and onset age follows the same general curve in all of them, implying a common mechanism not tied to glutamine.
Research student Shai Kaplan in Prof. Ehud Shapiro's lab in the institute's biological chemistry department and the computer sciences and applied mathematics department realized the answer might lie in somatic mutations - changes in the number of DNA repeats that build up in our cells. The longer the sequence, the greater the chance of additional mutation, and the scientists realized that the genes carrying the disease code might be accumulating more and more DNA repeats, until some critical threshold is crossed.
Based on the literature on some 20 known trinucleotide repeat diseases and their knowledge of the mechanisms governing somatic mutation, Shapiro, Kaplan (also in the molecular cell biology department), and Dr. Shalev Itzkovitz created a computer simulation that could take a given number of genetic repeats and show both the age of onset and the way in which the disease would progress. Their findings were recently presented in PLoS Computational Biology.
The new disease model appears to fit all the facts and to provide a good explanation for the onset and progression of all the known trinucleotide repeat diseases. Lab experiments could test this model, say the scientists and, as it predicts that all these diseases operate by somatic expansion of a trinucleotide repeat, it also suggests that a cure for all might be found in a drug or treatment that slows the expansion process.
Source: Judy Siegel-Itzkovich. Weizmann scientists move to defuse Huntington's time bomb. JPost.com (15 December 2007) [FullText]
Labels: Rehovot Science
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