Dr Thomas Massey

2021 Post-doctoral Clinical Fellowship

Using genetic modifiers to investigate the molecular mechanisms of repeat expansion in Huntington’s disease

Huntington’s disease (HD) is a degenerative disorder of the brain characterised by progressive involuntary movements, psychiatric problems, and eventually dementia. It affects about 1 in 8,000 people in the UK and is untreatable, leading to premature death after 10-20 years of debilitating decline. HD is an inherited condition caused by an abnormally long stretch of consecutive ‘CAG’ repeats in the DNA. The more repeats you have, the earlier in life the disease starts- but there is considerable variation. Repeats also expand further in the brains of people with HD, and this process probably causes earlier onset of disease symptoms. It is driven by factors like DNA repair proteins MSH3 and MLH1 but is not well understood. If we could understand the biochemical reactions that cause CAG repeats to expand, we could develop new drugs to target this process and potentially slow onset and progression of HD. My Fellowship project takes two approaches to understanding repeat biology. First, we will use induced pluripotent stem cells from a patient with 109 CAG repeats as a model system of repeat expansion. When we grow these cells in the laboratory the repeats expand, allowing us to discover the critical factors that drive this pathogenic process. We will use specific antibodies to pull out MLH1 and MSH3 proteins from these cells before identifying attached proteins that might be novel factors, and potential drug targets, in repeat expansions. Secondly, we will use extracts from these cells on artificial DNA substrates with CAG repeats to develop a rapid laboratory test of expansions that we hope will speed up research and aid therapeutic development.

Thomas was awarded the MRC Clinician Scientist Fellowship in 2023. He is also a group leader in the UK DRI at Cardiff .

Publications

Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset

McAllister, B., Donaldson, J., Binda, C.S. et al.

Nature Neuroscience 25, 446-457; doi: 10.1038/s41593-022-01033-5

2022

Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1

2. Lobanov, S, McAllister, B, McDade-Kumar, G, Landwehrmeyer, GB, Rosser, AE, Paulsen, JS, Lee, J-M, MacDonald, ME, Gusella, JF, Ryten, M, Williams, N, Holmans, P, Massey, TH & Jones, L

NPJ Genomic Medicine, 7, 53, https://doi.org/10.1038/s41525-022-00317-w

2022

Repeat Detector: versatile sizing of expanded tandem repeats and identification of interrupted alleles from targeted DNA sequencing

Alysha S Taylor, Dinis Barros, Nastassia Gobet, Thierry Schuepbach, Branduff McAllister, Lorene Aeschbach, Emma L Randall, Evgeniya Trofimenko, Eleanor R Heuchan, Paula Barszcz, Marc Ciosi, Joanne Morgan, Nathaniel J Hafford-Tear, Alice E Davidson, Thomas H Massey, Darren G Monckton, Lesley Jones, REGISTRY Investigators of the European Huntington’s disease network, Ioannis Xenarios, Vincent Dion

NAR Genomics and Bioinformatics, Volume 4, Issue 4, December 2022, lqac089, https://doi.org/10.1093/nargab/lqac089

2022

Genetic modifiers of Huntington disease differentially influence motor and cognitive domains

4. Lee, JM, Huang, Y et. al.

American Society of Human Genetics 2022 May 5;109(5):885-899. doi: 10.1016/j.ajhg.2022.03.004. Epub 2022 Mar 23. PMID: 35325614; PMCID: PMC9118113.

2022

Neurological consultation with an autistic patient

5. Cooper, M, Gale, K, Langley, K, Broughton T, Massey, TH, Hall, NJ & Jones, CRG

Practical Neurology 22, 120-125. doi: 10.1136/practneurol-2020-002856

2022

Author Response: Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease

Massey, TH, McAllister, B, Rosser, AE & Jones, L

Neurology, 98, 515. doi: 10.1212/WNL.0000000000200162

2022