SCA8 repeat expansion: large CTA/CTG repeat alleles in neurological disorders and functional implications.
Spinocerebellar ataxia type 8 (SCA8) involves bidirectional expression of CUG (ATXN8OS) and CAG (ATXN8) expansion transcripts. The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad. In the present study, we assessed the SCA8 repeat size ranges in Taiwanese Parkinson's disease, Alzheimer's disease and atypical parkinsonism and investigated the genetic variation modulating ATXN8 expression. Thirteen large SCA8 alleles and a novel ATXN8 -62 G/A promoter SNP were found. There is a significant difference in the proportion of the individuals carrying SCA8 larger alleles in atypical parkinsonism (P = 0.044) as compared to that in the control subjects. In lymphoblastoid cells carrying SCA8 large alleles, treatment of MG-132 or staurosporine significantly increases the cell death or caspase 3 activity. Although expressed at low steady-state, ATXN8 expression level is significantly higher (P = 0.012) in cells with SCA8 large alleles than that of the control cells. The ATXN8 transcriptional activity was significantly higher in the luciferase reporter construct containing the -62G allele than that containing the -62A allele in both neuroblastoma and embryonic kidney cells. Therefore, our preliminary results suggest that ATXN8 gene -62 G/A polymorphism may be functional in modulating ATXN8 expression.
Wu
Yih-Ru
YR
Department of Neurology, Chang Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, 10507, Taiwan.
Chen
I-Cheng
IC
Soong
Bing-Wen
BW
Kao
Shih-Huan
SH
Lee
Ghin-Chueh
GC
Huang
Shu-Yi
SY
Fung
Hon-Chung
HC
Lee-Chen
Guey-Jen
GJ
Chen
Chiung-Mei
CM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D002493:Central Nervous System Diseases / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D020754:Spinocerebellar Ataxias / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology; D013449:Sulfonamides; D019680:Trinucleotide Repeat Expansion
C539186:ATXN8 protein, human; C415906:ATXN8OS gene product, human; D017931:DNA Primers; C412617:KLHL1 protein, human; D007976:Leupeptins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D011743:Pyrimidines; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D013449:Sulfonamides; C113972:T 0201; D019311:Staurosporine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde