Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity

Morales Montero, F. et al. (2012) Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Human Molecular Genetics, 21(16), pp. 3558-3567. (doi: 10.1093/hmg/dds185)

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Deciphering the contribution of genetic instability in somatic cells is critical to our understanding of many human disorders. Myotonic dystrophy type 1 (DM1) is one such disorder that is caused by the expansion of a CTG repeat that shows extremely high levels of somatic instability. This somatic instability has compromised attempts to measure intergenerational repeat dynamics and infer genotype–phenotype relationships. Using single-molecule PCR, we have characterized more than 17 000 de novo somatic mutations from a large cohort of DM1 patients. These data reveal that the estimated progenitor allele length is the major modifier of age of onset. We find no evidence for a threshold above which repeat length does not contribute toward age at onset, suggesting pathogenesis is not constrained to a simple molecular switch such as nuclear retention of the DMPK transcript or haploinsufficiency for DMPK and/or SIX5. Importantly, we also show that age at onset is further modified by the level of somatic instability; patients in whom the repeat expands more rapidly, develop the symptoms earlier. These data establish a primary role for somatic instability in DM1 severity, further highlighting it as a therapeutic target. In addition, we show that the level of instability is highly heritable, implying a role for individual-specific trans-acting genetic modifiers. Identifying these trans-acting genetic modifiers will facilitate the formulation of novel therapies that curtail the accumulation of somatic expansions and may provide clues to the role these factors play in the development of cancer, aging and inherited disease in the general population.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Wilson, Dr Richard and Morales Montero, Mr Fernando and Adam, Mrs Berit and Higham, Dr Catherine and Couto, Dr Jillian and Monckton, Professor Darren and Braida, Mrs Claudia
Authors: Morales Montero, F., Couto, J.M., Higham, C.F., Hogg, G., Cuenca, P., Braida, C., Wilson, R.H., Adam, B., del Valle, G., Brian, R., Sittenfeld, M., Ashizawa, T., Wilcox, A., Wilcox, D.E., and Monckton, D.G.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Science and Engineering > School of Engineering > Infrastructure and Environment
College of Science and Engineering > School of Mathematics and Statistics
Journal Name:Human Molecular Genetics
ISSN (Online):1460-2083

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