Document Detail


Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17.
MedLine Citation:
PMID:  18043721     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Trinucleotide repeat expansions are dynamic mutations causing many neurological disorders, and their instability is influenced by multiple factors. Repeat configuration seems particularly important, and pure repeats are thought to be more unstable than interrupted repeats. But direct evidence is still lacking. Here, we presented strong support for this hypothesis from our studies on spinocerebellar ataxia type 17 (SCA17). SCA17 is a typical polyglutamine disease caused by CAG repeat expansion in TBP (TATA binding protein), and is unique in that the pure expanded polyglutamine tract is coded by either a simple configuration with long stretches of pure CAGs or a complex configuration containing CAA interruptions. By small pool PCR (SP-PCR) analysis of blood DNA from SCA17 patients of distinct racial backgrounds, we quantitatively assessed the instability of these two types of expanded alleles coding similar length of polyglutamine expansion. Mutation frequency in patients harboring pure CAG repeats is 2-3 folds of those with CAA interruptions. Interestingly, the pure CAG repeats showed both expansion and deletion while the interrupted repeats exhibited mostly deletion at a significantly lower frequency. These data strongly suggest that repeat configuration is a critical determinant for instability, and CAA interruptions might serve as a limiting element for further expansion of CAG repeats in SCA17 locus, suggesting a molecular basis for lack of anticipation in SCA17 families with interrupted CAG expansion.
Authors:
Rui Gao; Tohru Matsuura; Mary Coolbaugh; Christine Zühlke; Koichiro Nakamura; Astrid Rasmussen; Michael J Siciliano; Tetsuo Ashizawa; Xi Lin
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-11-28
Journal Detail:
Title:  European journal of human genetics : EJHG     Volume:  16     ISSN:  1018-4813     ISO Abbreviation:  Eur. J. Hum. Genet.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-01-17     Completed Date:  2008-04-22     Revised Date:  2013-12-17    
Medline Journal Info:
Nlm Unique ID:  9302235     Medline TA:  Eur J Hum Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  215-22     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Female
Genomic Instability*
Humans
Male
Middle Aged
Spinocerebellar Ataxias / classification,  genetics*
TATA-Box Binding Protein / genetics
Trinucleotide Repeat Expansion / genetics*
Grant Support
ID/Acronym/Agency:
CA112508/CA/NCI NIH HHS; NS41547/NS/NINDS NIH HHS; R01 NS041547/NS/NINDS NIH HHS; R01 NS041547-07/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/TATA-Box Binding Protein; 0/TBP protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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