PubMed:26994442 JSONTXT 8 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 184-396 DRI_Outcome denotes Somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 is age-dependent, tissue-specific and expansion-biased, contributing toward the tissue-specificity and progressive nature of the symptoms.
T2 397-637 DRI_Approach denotes 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.
T3 638-745 DRI_Outcome denotes Here, we confirm these results using a larger more genetically homogenous Costa Rican DM1 cohort (p<0.001).
T4 746-905 DRI_Outcome denotes Interestingly, we also provide evidence that supports subtle sex-dependent differences in repeat length-dependent age at onset and somatic mutational dynamics.
T5 906-1017 DRI_Outcome denotes Previously, we demonstrated that variation in the rate of somatic expansion was a heritable quantitative trait.
T6 1018-1254 DRI_Outcome denotes 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).
T7 1255-1471 DRI_Background denotes 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).
T8 1472-1570 DRI_Approach denotes However, only the association with Rs26279 remained significant after multiple testing correction.
T9 1571-1728 DRI_Outcome denotes Although we revealed a statistically significant association between Rs26279 and somatic instability, we did not detect an association with the age at onset.
T10 1729-1857 DRI_Outcome denotes Individuals with the A/A genotype for Rs26279 tended to show a greater propensity to expand the CTG repeat than other genotypes.
T11 1858-1994 DRI_Outcome denotes Interestingly, this SNP results in an amino acid change in the critical ATPase domain of MSH3 and is potentially functionally dimorphic.
T12 1995-2149 DRI_Challenge denotes 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.