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dc.creatorHigham, Catherine
dc.creatorHogg, Grant
dc.creatorBraida, Claudia
dc.creatordel Valle Carazo, Gerardo
dc.creatorBrian Gago, Roberto
dc.creatorSittenfeld Appel, Mauricio
dc.creatorAshizawa, Tetsuo
dc.creatorWilcox, Alison
dc.creatorCouto, Jillian M.
dc.creatorMorales Montero, Fernando
dc.creatorCuenca Berger, Patricia
dc.creatorWilson, Richard H.
dc.creatorAdam, Berit
dc.creatorWilcox, Dougals E.
dc.creatorMonckton, Darren G.
dc.date.accessioned2013-12-04T16:07:27Z
dc.date.available2013-12-04T16:07:27Z
dc.date.issued2012-05-30
dc.identifier.citationhttp://hmg.oxfordjournals.org/content/21/16/3558.full.pdf+html
dc.identifier.issn0964-6906
dc.identifier.otheressn:1460-2083
dc.identifier.urihttps://hdl.handle.net/10669/8924
dc.descriptionartículo (arbitrado) -- Universidad de Costa Rica. Instituto de investigaciones en Salud, 2012. Este artículo es privado debido a limitaciones de derecho de autor.es
dc.description.abstractDeciphering 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.es
dc.description.sponsorshipInstitute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences and School of Mathematics and Statistics, University of Glasgow. Instituto de Investigaciones en Salud y Escuela de Medicina de la Universidad de Costa Rica. Servicio de Neurología, Hospital Nacional de Niños. Servicio de Neurología, Hospital San Juan de Dios. Laboratorio de Neurofisiología (Neurolab). Department of Neurology, University of Florida. Ferguson-Smith Centre for Clinical Geneticses
dc.language.isoen_USes
dc.publisherHuman Molecular Genetics, 2012 Vol. 21, No. 16. 3558–3567es
dc.subjectMutaciónes
dc.subjectGenéticaes
dc.subjectEtiologíaes
dc.subjectGenotipoes
dc.subjectFenotipoes
dc.subjectCélula somáticaes
dc.titleSomatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severityes
dc.typeartículo científico
dc.identifier.doi10.1093/hmg/dds185
dc.description.procedenceUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)es


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