Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver 英文参考文献.docVIP

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Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver 英文参考文献.doc

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Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver 英文参考文献

QuantificationofAge-DependentSomaticCAGRepeat InstabilityinHdhCAGKnock-InMiceRevealsDifferent ExpansionDynamicsinStriatumandLiver Jong-MinLee*.,RicardoMouroPinto.,TammyGillis,JasonC.St.Claire,VanessaC.Wheeler* CenterforHumanGeneticResearch,MassachusettsGeneralHospital,Boston,Massachusetts,UnitedStatesofAmerica Abstract Background:AgeatonsetofHuntington’sdisease(HD)islargelydeterminedbytheCAGtrinucleotiderepeatlengthinthe HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understandingunderlyingmechanismsofsomaticCAGrepeatinstabilitymayleadtodiscoveriesofnoveltherapeuticsfor HD. Investigation of thedynamics of the CAG repeat size changes overtime may provide insights into the mechanisms underlyingCAGrepeatinstability. Methodology/PrincipalFindings:TounderstandhowtheHTTCAGrepeatlengthchangesovertime,wequantifiedsomatic instabilityoftheCAGrepeatinHuntington’sdiseaseCAGknock-inmicefrom2–16monthsofageinliver,striatum,spleen andtail.TheHTTCAGrepeatinspleenandtailwasverystable,butthatinliverandstriatumexpandedovertimeatan average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum.UnstableCAGrepeatsinliverrepeatedlygainedsimilarsizesofadditionalCAGrepeats(approximatelytwoCAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additionalrepeatswithdifferentsizesresultinginbroadlydistributedunstableCAGrepeats.ExpandedCAGrepeatsinthe liverwerehighlyenrichedinpolyploidhepatocytes,suggestingthatthepatternofliverinstabilitymayreflecttherestriction oftheunstablerepeatstoauniquecelltype. Conclusions/Significance:Ourresultsareconsistentwithrepeatexpansionoccurringasaconsequenceofrecurrentsmall repeat insertions that differ in different tissues. Investigation of th