Document Detail


High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles.
MedLine Citation:
PMID:  10712199     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-onset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8. We have now (1) assessed the repeat size in a group of patients with ataxia and a large number of controls, (2) examined the intergenerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alleles; large alleles accounted for only0.7% of all normal-size alleles. No expanded alleles (>/=100 CTGs) were found in controls. Expansion of the CTG tract was found in five families with ataxia; expanded alleles (all paternally transmitted) were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus.
Authors:
I Silveira; I Alonso; L Guimarães; P Mendonça; C Santos; P Maciel; J M Fidalgo De Matos; M Costa; C Barbot; A Tuna; J Barros; L Jardim; P Coutinho; J Sequeiros
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of human genetics     Volume:  66     ISSN:  0002-9297     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2000 Mar 
Date Detail:
Created Date:  2000-04-20     Completed Date:  2000-04-20     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  830-40     Citation Subset:  IM    
Affiliation:
UnIGENe, IBMC, 4150-180 Porto, Portugal. isilveir@ibmc.up.pt
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Age of Onset
Aged
Alleles*
Child
Child, Preschool
Female
Gene Frequency / genetics
Genetic Counseling
Genetic Variation / genetics
Haplotypes
Humans
Male
Meiosis / genetics
Microsatellite Repeats / genetics
Middle Aged
Mitosis / genetics
Mutagenesis / genetics
Pedigree
Penetrance
Spermatogenesis / genetics
Spermatozoa / metabolism*
Spinocerebellar Ataxias / epidemiology,  genetics*,  physiopathology
Trinucleotide Repeat Expansion / genetics*
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