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dc.creatorMorales Montero, Fernando
dc.creatorVásquez Cerdas, Melissa
dc.creatorSantamaría Ulloa, Carolina
dc.creatorCuenca Berger, Patricia
dc.creatorCorrales Acuña, Eyleen Vanessa
dc.creatorMonckton, Darren G.
dc.date.accessioned2018-07-18T16:54:24Z
dc.date.available2018-07-18T16:54:24Z
dc.date.issued2016-04
dc.identifier.citationhttps://www.sciencedirect.com/science/article/pii/S156878641530063X?via%3Dihubes_ES
dc.identifier.issn1568-7864
dc.identifier.urihttps://hdl.handle.net/10669/75219
dc.description.abstractSomatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 is age-dependent, tissuespecific and expansion-biased, contributing toward the tissue-specificity and progressive nature of the symptoms. Previously, using regression modelling of repeat instability we showed that variation in the rate of somatic expansion in blood DNA contributes toward variation in age of onset, directly implicating somatic expansion in the disease pathway. Here, we confirm these results using a larger more genetically homogenous Costa Rican DM1 cohort (p < 0.001). Interestingly, we also provide evidence that supports subtle sex-dependent differences in repeat length-dependent age at onset and somatic mutational dynamics. Previously, we demonstrated that variation in the rate of somatic expansion was a heritable quantitative trait. Given the important role that DNA mismatch repair genes play in mediating expansions in mouse models, we tested for modifier gene effects with 13 DNA mismatch gene polymorphisms (one each in MSH2, PMS2, MSH6 and MLH1; and nine in MSH3). After correcting for allele length and age effects, we identified three polymorphisms in MSH3 that were associated with variation in somatic instability: Rs26279 (p = 0.003); Rs1677658 (p = 0.009); and Rs10168 (p = 0.031). However, only the association with Rs26279 remained significant after multiple testing correction. Although we revealed a statistically significant association between Rs26279 and somatic instability, we did not detect an association with the age at onset. Individuals with the A/A genotype for Rs26279 tended to show a greater propensity to expand the CTG repeat than other genotypes. Interestingly, this SNP results in an amino acid change in the critical ATPase domain of MSH3 and is potentially functionally dimorphic. These data suggest that MSH3 is a key player in generating somatic variation in DM1 patients and further highlight MSH3 as a potential therapeutic target.es_ES
dc.language.isoen_USes_ES
dc.sourceDNA Repair, Vol. 40, pp 57-66es_ES
dc.subjectMyotonic dystrophyes_ES
dc.subjectSomatic mosaicismes_ES
dc.subjectModifier genees_ES
dc.subjectDNA mismatch repaires_ES
dc.subjectSimple sequence repeates_ES
dc.subjectTrinucleotide repeates_ES
dc.subject616.74 Enfermedades de los músculoses_ES
dc.subjectHuman geneticses_ES
dc.titleA polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patientses_ES
dc.typeartículo científicoes_ES
dc.identifier.doi10.1016/j.dnarep.2016.01.001
dc.description.procedenceUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)es_ES
dc.description.procedenceUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN)es_ES
dc.description.procedenceUCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Nutriciónes_ES


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