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UI Researchers Selectively Silence Disease-Causing Gene


Genes come in pairs, one copy from your mom and one from your dad. In some genetic conditions, inheriting one bad, or mutant, gene copy from either parent is sufficient to cause disease. University of Iowa researchers have shown that it is possible to silence a mutant gene without affecting expression of the normal gene.

The findings suggest that the gene-silencing technique might one day be useful in treating many human diseases, including cancer, Huntington’s disease and similar genetic disorders, and viral diseases, where it would be desirable to selectively turn off certain genes that cause problems.

In particular, the UI researchers were able to silence mutant genes without affecting the normal gene copy even when the mutant and the normal gene differ by as little as a single letter in the genetic code. The study will appear this week in the Online Early Edition of the Proceedings of the National Academy of Sciences (

"If you have a bad gene, you simply switch it off and leave the good copy alone to perform its normal function," said Victor Miller, a UI graduate student and the lead author of the paper. "It is an intellectually simple but technically difficult thing to do. We have shown that a single nucleotide difference between a normal gene and a mutant gene can be used to turn off the mutant gene and spare expression of the normal gene.

"This work is an important proof of principle but it is still a long way from clinical application," Miller added.

Turning off a mutant gene while keeping the normal gene active would be particularly useful in therapies aimed at treating so-called dominantly inherited diseases. In these diseases, a single mutant copy of a gene inherited from either parent dominates the normal gene by producing a protein that is toxic to cells. Thus, a successful therapy must remove or suppress the disease-gene rather than simply add a corrected version. At the same time, the normal gene may be essential, so it is important to be able to silence the disease-causing gene without affecting the normal copy. Many neurodegenerative conditions, including Huntington’s disease (HD), are dominantly inherited. The HD gene also is an example of a normal gene that appears to be essential for normal function.

Working in cell culture, the UI researchers used the relatively new technology known as RNA interference to silence a mutant gene that causes the neurodegenerative condition called Machado-Joseph disease (or Spinocerebellar Ataxia Type 3), while leaving the normal gene alone.

Machado-Joseph disease (MJD), Huntington’s disease and at least seven other neurodegenerative disorders all are caused by the same type of genetic mutation. The genetic defect in these diseases produces a mutated protein with an abnormally long stretch of a repeated amino acid. The mutant protein in each of these conditions is prone to clump together, forming aggregates, which appear to damage brain tissue. Other neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, also are characterized by a tendency for proteins to misfold or clump in the brain. The UI team studies Machado-Joseph disease because it is a good model for investigating these types of neurodegenerative diseases.

Initial attempts to silence the mutant MJD gene by targeting the RNA interference to the repeat-expansion mutation failed. So the UI researchers focused on a single sequence difference, also known as a single nucleotide polymorphism (SNP), which occurs just next to the mutated sequence in about 70 percent of mutant MJD genes.

"When we tried to target the mutation itself, the interfering RNA was not able to distinguish the mutant gene from the normal gene and both copies were suppressed," said Henry Paulson, M.D., Ph.D., UI assistant professor of neurology and principle investigator of the study. "Then we noticed that there was a single nucleotide polymorphism in the mutant MJD gene that comes right after the mutation in most cases. We targeted that single nucleotide variation with RNA interference and that approach was able to distinguish the mutant from the normal and only knock down the mutant gene."

Paulson added that the discovery that RNA interference could distinguish between genes on the basis of a single nucleotide polymorphism was very exciting because every person’s DNA differs mostly on the basis of these unique single letter variations in the genetic code. Thus it might be possible to use RNA interference to target unique single nucleotide polymorphisms associated with specific genes in order to manipulate those genes.

"Even when one cannot target a disease-causing mutation, it may still be possible to target the mutant gene on the basis of a SNP associated with that gene," Paulson said.

The research team also used RNA interference to target an actual disease-causing mutation due to a single base pair change in a gene. Tau is an important cellular protein that is mutated in some inherited dementias that are somewhat similar to Alzheimer’s disease. The UI researchers directed RNA interference against a specific mutation in the Tau gene that is known to cause dementia in people. Again, the approach was successful in silencing only the mutant gene and not the normal gene.

"RNA interference is an exciting new tool that may have therapeutic value," Paulson said. "We have provided one more advance in the progress toward making this a potential therapy. If we can use this to target a disease gene exclusively, that will be very valuable."

In addition to Miller and Paulson, the UI research team included Haibin Xia, Ph.D., Ginger Marrs, Cynthia Gouvion, Gloria Lee, Ph.D., and Beverly Davidson, Ph.D., the Roy J. Carver Chair in Internal Medicine, and UI professor in internal medicine, neurology, and physiology and biophysics.

The research was funded by grants from the National Institutes of Health.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at

Jennifer Brown | University of Iowa
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