Michael Hayden

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This week we profile a recent publication in The American Journal of Human Genetics from the
laboratory of Dr. Michael Hayden (pictured) at the Centre for Molecular Medicine and Therapeutics.

Can you provide a brief overview of your lab’s current research focus?

My research group at the University of British Columbia (UBC) uses genetics to help inform the diagnosis and treatment of disease. A particular area of emphasis in this regard involves the study of the neurodegenerative disorder, Huntington disease (HD), which affects approximately 1 in 7,000 Canadians. For every affected person, there are approximately three to four individuals that carry the mutation, but have not yet developed the disease. HD is caused by an expanded stretch of the amino acid glutamine in the huntingtin gene; the longer this string of amino acids, the earlier patients tend to present with the disorder on average. The disorder displays an autosomal dominant pattern of inheritance, meaning that if one of your parents is affected, you have a 50% chance of carrying the disease-causing mutation. Patients typically present with the disorder, which is characterized by movement, cognitive and psychiatric impairments, in their forties. Our research in HD covers various aspects of the disorder, from studying the underlying biological mechanisms, to developing gene therapy based approaches that aim to target the mutated copy of huntingtin.

What is the significance of the findings in this publication?

In the current study, we wanted to investigate how HD patients with identical polyglutamine lengths, can present with the disorder at very different ages, sometimes decades apart. Consequently, there is the potential to identify additional genetic modifiers of the disorder.

This study focused on the area surrounding the pathogenic polyglutamine repeat, which is predominantly encoded in the DNA by CAG codons. However, the penultimate codon in this region is usually a glutamine-related CAA motif. In a subset of HD patients that presented significantly earlier than expected based on their polyglutamine length, we identified a genetic variant where this codon had undergone a single substitution from CAA to CAG, increasing the length of the uninterrupted CAG repeat. Of clinical significance, carriers of this loss of interruption variant presented with HD decades earlier than expected on average. Conversely, we also identified an additional variant where the final extra CAA interruption was duplicated, which was associated with a delayed onset of the disorder in patients that carry this variant.

But how do changes on the DNA level that do not influence protein sequence alter clinical onset of HD? We believe that a process known as somatic instability could be responsible. This arises since long stretches of repetitive DNA are difficult for cells to copy and repair. Consequently, the length of the disease-causing repeat to expand in certain cells in the body, particularly in the brain. In HD, this leads to a mutated protein with an extended polyglutamine tract. An increasing number of studies are showing that this is a significant process in Huntington disease. When we assessed the loss of interruption variant in the blood of HD patients, we found that the CAG repeat was more unstable in these individuals, providing the first insights into the potential mechanism behind this finding.

It has now become clear that uninterrupted CAG length is more relevant than polyglutamine size and is more accurate in predicting age of onset in HD. This observation could only have been made through the valuable contributions from HD families and a strong network of collaborators. The current study was led by a UBC research associate, Galen Wright, along with key contributions from two of my other lab members, Jennifer Collins and Chris Kay.

What are the next steps for this research?

We are currently working with collaborators to gain access to post mortem brain tissue from HD patients that carry the variant of interest in order to study somatic instability in the most disease-relevant tissues. Another area of focus is to systematically screen more HD patients for these two variants to further refine our estimates with regards to their impact on modifying age of onset. In order to achieve this, we are developing efficient strategies to screen these variants in larger groups of HD patients. Additionally, we have another study that is investigating how other genes in our genome can also modify HD clinical onset. Each step brings us closer to improving the management of HD.

This work was funded by:

This work was supported by my Canadian Institutes of Health Research Foundation grant. I am also a Killam Professor and founder of the Centre for Molecular Medicine and Therapeutics (CMMT) at UBC and a Canadian Research Chair in Human Genetics and Molecular Medicine.

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