Document Detail

SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance.
MedLine Citation:
PMID:  10958651     Owner:  NLM     Status:  MEDLINE    
We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission.
M L Moseley; L J Schut; T D Bird; M D Koob; J W Day; L P Ranum
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Human molecular genetics     Volume:  9     ISSN:  0964-6906     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2000 Sep 
Date Detail:
Created Date:  2000-09-29     Completed Date:  2000-11-21     Revised Date:  2010-09-22    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  2125-30     Citation Subset:  IM    
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
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MeSH Terms
Blotting, Southern
Family Health
Gene Duplication
Models, Genetic
Nerve Tissue Proteins / biosynthesis,  genetics*
Sequence Analysis, DNA
Spermatozoa / metabolism*
Spinocerebellar Ataxias / genetics
Trinucleotide Repeat Expansion
Trinucleotide Repeats / genetics*
Grant Support
Reg. No./Substance:
0/ATXN8OS gene product, human; 0/Nerve Tissue Proteins

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