CAG repeat not polyglutamine length determines timing of Huntington’s disease onset

Lee, J.-M. et al. (2019) CAG repeat not polyglutamine length determines timing of Huntington’s disease onset. Cell, 178(4), 887-900.e14. (doi: 10.1016/j.cell.2019.06.036)

Abstract

Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin’s polyglutamine segment, dictates the rate at which Huntington’s disease (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 the fundamental premise that polyglutamine length determines the rate of pathogenesis in the “polyglutamine disorders.”

• Item Type: Articles
• Additional Information: Supported by the CHDI Foundation (U.S.), the U.S. National Institutes of Health (NS082079, NS091161, NS016367, NS049206), the Medical Research Council (UK; MR/L010305/1 and fellowship MR/P001629/1), and a Cardiff University School of Medicine studentship.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Chatzi, Ms Afroditi and Maxwell, Mr Alastair and Monckton, Professor Darren and Ciosi, Dr Marc

Creator Roles

Ciosi, M.: Investigation, Writing – review and editing
Maxwell, A.: Investigation
Chatzi, A.: Investigation
Monckton, D. G.: Writing – review and editing, Supervision

• Authors: 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. G., Pinto, R. M., Abu Elneel, K., Ramos, E. M., Mysore, J. S., Gillis, T., Wheeler, V. C., MacDonald, M. E., Gusella, J. F., McAllister, B., Massey, T., Medway, C., Stone, T. C., Hall, L., Jones, L., Holmans, P., Kwak, S., Ehrhardt, A. G., Sampaio, C., Ciosi, M., Maxwell, A., Chatzi, A., Monckton, D. G., Orth, M., Landwehrmeyer, G. B., Paulsen, J. S., Dorsey, E. R., Shoulson, I., and Myers, R. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 0092-8674
• ISSN (Online): 1097-4172
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Cell 178(4): 887-900.e14
• Publisher Policy: Reproduced under a Creative Commons License