Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis.
Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Although the mutant protein is widely expressed, the earliest and most striking neuropathological changes are observed in the striatum. Here we show dramatic mutation length increases (gains of up to 1000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathological cell loss. Studies of knock-in HD mouse models indicate that the size of the initial CAG repeat mutation may influence both onset and tissue-specific patterns of age-dependent, expansion-biased mutation length variability. Given that CAG repeat length strongly correlates with clinical severity, we suggest that somatic increases of mutation length may play a major role in the progressive nature and cell-selective aspects of both adult-onset and juvenile-onset HD pathogenesis and we discuss the implications of this interpretation of the data presented.
Division of Molecular Genetics, Faculty of Biomedical and Life Scienes, University of Glasgow, Anderson College Complex, 56 Dumbarton Road, Glasgow G11 6NU, UK.
Laura
L
Kennedy
Elizabeth
E
Evans
Chiung-Mei
CM
Chen
Lyndsey
L
Craven
Peter J
PJ
Detloff
Margaret
M
Ennis
Peggy F
PF
Shelbourne
D000367:Age Factors; D000483:Alleles; D000818:Animals; D001921:Brain / Q000648:ultrastructure; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D019680:Trinucleotide Repeat Expansion
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins