A New Light On Huntington's Disease

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Scientists at the Weizmann Institute have proposed a mechanism that provides an explanation for the remarkable precision of the genetic time bomb causing Huntington's and other trinucleotide repeat diseases.

The research, led by Prof. Ehud Shapiro, revealed the genetic model of these diseases, which might help researchers towards a possible prevention or cure of such an incurable disease.

Huntington's disease is a genetic time bomb, which is programmed in the genes. It appears at a predictable age in adulthood, causing a progressive decline in mental and neurological function and finally leading to death. There is, to date, no cure.

Huntington's and a number of diseases like it, collectively known as trinucleotide repeat diseases, are caused by an unusual genetic mutation: A three-letter piece of gene code is repeated over and over in one gene.

In Huntington's patients, the number of repeats ranges from 40 to over 70. It was noted by the scientists that, like clockwork, one can predict the no of times the sequence repeats in a patient's gene – both the age at which the disease will appear and how quickly the disease 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 eventually reaching toxic levels.

Unfortunately, this theory, 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 display symptoms earlier than those with a single copy. Also, 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 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 throughout our lives.

The length of the sequence was directly proportional to the hance of additional mutation. That means: 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 over time, until some critical threshold is crossed.

Depending on the literature on some 20 known trinucleotide repeat diseases and their knowledge of the mechanisms governing somatic mutation, Shapiro, Kaplan (who is 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 progresses.

This new disease model appears to fit all of the facts and to provide a good explanation for the onset and progression of all of the known trinucleotide repeat diseases.

The scientists said that the model could be tested through experimentation in research labs 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 down the expansion process.

Disclaimer: The information provided in this article is for general informational and educational purposes only and is not intended as a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or a qualified healthcare provider with any questions you may have regarding a medical condition.