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Haplotype diversity and somatic instability in normal and expanded SCA8 alleles
Author(s) -
Martins Sandra,
Seixas Ana I.,
Magalhães Paula,
Coutinho Paula,
Sequeiros Jorge,
Silveira Isabel
Publication year - 2005
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30235
Subject(s) - haplotype , genetics , biology , penetrance , spinocerebellar ataxia , trinucleotide repeat expansion , population , allele , gene , medicine , environmental health , phenotype
Abstract Spinocerebellar ataxia type 8 (SCA8) is an autosomal dominant late‐onset neurodegenerative disorder, belonging to the group of diseases caused by trinucleotide repeat expansions. SCA8 remains one of the most intriguing SCAs, regarding the reduced disease penetrance, and the high instability and poorly understood functional meaning of the (CTA) n (CTG) n expansion. We performed haplotype and sequencing analysis in a large region, encompassing the repeat, in four SCA8 and 20 control Portuguese families. The results from the haplotype study including the combined repeat and six SNP markers showed two different haplotypes, AG‐Exp‐GTTG and AG‐Exp‐CTTG, in the SCA8 families. Among the control population, these were also the most frequent, in a total of five haplotypes found unequally distributed throughout repeat sizes. From cloning fragments of control, unstable normal and expanded chromosomes, eleven different base substitutions were identified in exon A of the SCA8 gene. In some instances, somatic variability in repeat size or base composition was found for a same chromosome, regardless of its normal or expanded nature. In conclusion, our results in Portuguese families with ataxia show that SCA8 expansions arose in common backgrounds; in addition, this region seems to be unstable beyond the repeat. © 2005 Wiley‐Liss, Inc.