Blair Leavitt
Huntington’s disease is caused by a mutation in the Huntington’s disease gene, but it has long been a mystery why some people with the exact same mutation get the disease more severely and earlier than others.
Blair Leavitt, a Professor in the Department of Medical Genetics, and his colleagues took a closer look at the DNA surrounding the HD gene — regions where proteins, called transcription factors, can bind to the DNA and control the gene’s function.
In some cases, the DNA variations increase the severity of the disease and speed up its onset; in other cases, these changes delay the onset of the disease.
“The gene for Huntington’s was discovered over twenty years ago but there is very little known about how the expression of this important gene is controlled,” said Dr. Leavitt, who is also a scientist with the Centre for Molecular Medicine and Therapeutics. “This study helps us understand how small genetic differences in the DNA surrounding the HD gene can both delay and accelerate the disease.”
Huntington’s disease gets passed down in families, but symptoms generally don’t appear until later in life. It affects the brain and gradually worsens, causing problems with coordination and movement, mental decline and psychiatric issues. While every person has two copies of each gene – one on each chromosome – a single mutation in one copy of the HD gene means the person will suffer from the disease.
In a paper published May 4 in Nature Neuroscience, Dr. Leavitt and collaborators report that when the DNA variation is found on a normal chromosome with no HD mutation, it turns off the expression of the good gene and allows the mutant gene on the other chromosome to predominate, speeding up the onset of the disease. If the DNA change is found on a chromosome with the HD mutation, it turns off the bad gene and offers individuals some protection from the disease.
These findings provide critical evidence to support the development of new drugs that decrease the expression of the mutant HD gene, an approach called gene silencing, Dr. Leavitt says. He is already involved in the testing of one gene silencing treatment that shows great promise, and will begin the first human trial of this therapy for HD later this year.