UseCases_ArguminSci_Discourse  

PubMed:24204323 JSONTXT 11 Projects

Annnotations TAB TSV DIC JSON TextAE Lectin_function IAV-Glycan

Id Subject Object Predicate Lexical cue
T1 0-126 DRI_Challenge denotes Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.
T2 127-245 DRI_Outcome denotes The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis.
T3 246-432 DRI_Challenge denotes Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases.
T4 433-610 DRI_Background denotes Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ).
T5 611-870 DRI_Challenge denotes Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier.
T6 871-1072 DRI_Challenge denotes Crossing B6.Hdh(Q111) mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons.
T7 1073-1231 DRI_Background denotes Hdh(Q111) somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3) complex as a key driver of somatic expansion.
T8 1232-1416 DRI_Background denotes Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3).
T9 1417-1481 DRI_Background denotes The Mlh1 locus is highly polymorphic between B6 and 129 strains.
T10 1482-1666 DRI_Approach denotes While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent.
T11 1667-1775 DRI_Background denotes MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a
T12 1776-1805 Token_Label.OUTSIDE denotes dose-sensitive MLH1-dependent
T13 1806-1893 DRI_Background denotes DNA repair mechanism underlying the somatic expansion difference between these strains.
T14 1894-2214 DRI_Approach denotes Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.