Huntington's disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms

Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium,; Lee, J.-M.; Correia, K.; Loupe, J.; Kim, K.-H.; Barker, D.; Hong, E. P.; Chao, M. J.; Long, J. D.; Lucente, D.; Vonsattel, J.-P.; Mouro Pinto, R.; Abu Elneel, K.; Ramos, E. M.; Mysore, J. S.; Gillis, T.; Wheeler, V. C.; MacDonald, M. E.; Gusella, J. F.; Massey, T.; McAllister, B.; Medway, C.; Stone, T. C.; Hall, L.; Jones, L.; Holmans, P.; Kwak, S.; Ehrhardt, A.; Sampaio, C.; Ciosi, M.; Maxwell, A.; Chatzi, A.; Monckton, D. G.; Orth, M.; Landwehrmeyer, G. B.; Paulsen, J. S.; Dorsey, E. R.; Shoulson, I.; Myers, R. H.

doi:10.1101/529768

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bioRxiv · 10.1101/529768

Huntington's disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms

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Abstract

The effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtins polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the "polyglutamine disorders".

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Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium,, Lee, J.-M., Correia, K., Loupe, J., Kim, K.-H., Barker, D., Hong, E. P., Chao, M. J., Long, J. D., Lucente, D., Vonsattel, J.-P., Mouro Pinto, R., Abu Elneel, K., Ramos, E. M., Mysore, J. S., Gillis, T., Wheeler, V. C., MacDonald, M. E., Gusella, J. F., Massey, T., McAllister, B., Medway, C., Stone, T. C., Hall, L., Jones, L., Holmans, P., Kwak, S., Ehrhardt, A., Sampaio, C., Ciosi, M., Maxwell, A., Chatzi, A., Monckton, D. G., Orth, M., Landwehrmeyer, G. B., Paulsen, J. S., Dorsey, E. R., Shoulson, I., Myers, R. H.. 2019-01-24. Huntington's disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms. https://doi.org/10.1101/529768

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