FSHD A Repeat Contraction Disease Finally Ready to Expand (Our Understanding of Its Pathogenesis) 英文参考文献.docVIP

Perspective FSHD:ARepeatContractionDiseaseFinallyReadyto Expand(OurUnderstandingofItsPathogenesis) ChristopherE.Pearson1,2 * 1ProgramofGeneticsandGenomeBiology,TheHospitalforSickChildren,Toronto,Ontario,Canada,2DepartmentofMolecularGenetics,UniversityofToronto,Toronto, Ontario,Canada Facioscapulohumeral muscular dystro- phy (FSHD), was one of the first diseases showntobecausedbyanunstablerepeat in the early 1990s along with spinal and bulbar muscular atrophy (SBMA), myo- tonic dystrophy (DM1), and fragile X mental retardation (FRAXA), where the latter three are caused by genetically expandingtrinucleotiderepeats[1].How- ever, FSHDdiffers considerably fromthe trinuclotiderepeatdiseases,asitiscaused byacontractionofamacrosatellite(D4Z4 repeat, 3.3kb/unit). Moreover, far less is understood about the pathogenic mecha- nismforFSHD,relativetoSBMA,DM1, andFRAXA.Thisisnotduetoashortage of experimental efforts, plausible hypoth- eses, or collaborative efforts towards un- derstanding FSHD[2,3]. The elucidation of FSHD is hampered by the size of the unstable repeat, its sequence complexity, the number of repeat units, and the presence of the repeat on Chromosomes 4 and 10, making analysis technically difficult. The difficulty is compounded furtherbytheabsenceofanobviousgene, transcript, or protein in the unstable or proximalregion;infact,theD4Z4repeats have been referred to as ‘‘junk’’ DNA or arethoughttobeapseudogene,atbest.As aresult,FSHDhasprovedtobeoneofthe most complex and challenging genetic diseases to even a glimpse an underlying units, but must have at least one unit to show disease, which is now known to be the most telomeric unit. D4Z4 contrac- tionscanbeinheritedoroccurasdenovo mutations. The contracted D4Z4 repeat arraysshowlossofDNAmethylationand reducedhistone 3lysine 9trimethylation, consistent with a more open chromatin structure [5]. The role of the altered chromatin in FSHD pathogenesis is con- troversial and has been suggested to enhance expressi