SCA8 CAGCTG Expansions, a Tale of Two TOXICities A Unique or Common Case 英文参考文献.docVIP

Perspective SCA8CAG/CTGExpansions,aTaleofTwoTOXICities:A UniqueorCommonCase? KarineMerienne,YvonTrottier* Department of Neurobiology and Genetics, Institute of Genetics and Molecular and Cellular Biology (IGBMC), UMR 7104-CNRS/INSERM/UdS, BP10142, Illkirch, CU de Strasbourg,France Adozendominantgeneticdisordersare causedbyaberrantexpansionsofCAGor CTG trinucleotide repeats. As these re- peats are complementary sequences, the expansions are incurred by both strands. However, it is the genic or transcribed strand that has defined the CAG and CTGrepeatdiseases.CAGrepeat–associ- ated diseases represent a group of neuro- logical disorders, including Huntington’s disease, dentatorubral pallidoluysian atro- phy,spinal andbulbarmuscularatrophy, [5].Twoarticlesonspinocerebellarataxia type 8 (SCA8) published by the group of LauraRanum,firstin2006[6]andnowin thisissueofPLoS Genetics[7],suggestthat this view is simplistic, deserving of atten- tionandrevision. tein colocalizes with these RNA foci. Furthermore, the authors provide evi- dence for a genetic interaction between SCA8 and Mbnl1 gene loci by showing that loss of the Mbnl1 gene in SCA8 BACexp mice increases the motor pheno- type. These results extend to mice earlier observations in flies showing that SCA8 CUGtranscriptexpressioncausedtoxicity that can be modulated by mutation in muscle-blind or three other genes encoding RNA-binding proteins [9]. Importantly, using cross-linking and immunoprecipita- tion(CLIP)analysiswithananti-CUGBP1 antibody,Ranumandcolleaguesidentifya specificCUGBP1RNAtarget,theGABA- A transporter 4 (GAT4) transcript, which shows up-regulation and a shift in alter- nativesplicingfavoringexon7insertionin SCA8 mouse and patient brains, resem- bling expression features detected in the fetal cortex. Interestingly, these changes are specific to SCA8 patients, as GAT4 expressionandsplicingpatternarenormal in DM1 brain. Finally, up-regulation of theGAT4geneproduct,whichisprimarily detected in the granul