Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity
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Date
2012-05-30Author
Higham, Catherine
Hogg, Grant
Braida, Claudia
del Valle Carazo, Gerardo
Brian Gago, Roberto
Sittenfeld Appel, Mauricio
Ashizawa, Tetsuo
Wilcox, Alison
Couto, Jillian M.
Morales Montero, Fernando
Cuenca Berger, Patricia
Wilson, Richard H.
Adam, Berit
Wilcox, Dougals E.
Monckton, Darren G.
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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.
External link to the item
10.1093/hmg/dds185
artículo (arbitrado) -- Universidad de Costa Rica. Instituto de investigaciones en Salud, 2012. Este artículo es privado debido a limitaciones de derecho de autor.