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Identifying novel interruption motifs in spinocerebellar ataxia type 10 expansions
Author(s) -
Liu Jilin,
McFarland Karen N,
Landrian Ivette,
Wu Samuel S,
Bower Matthew,
Hutter Diane,
Bushara Khalaf,
Teive Hélio A G,
Ashizawa Tetsuo
Publication year - 2014
Publication title -
neurology and clinical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2049-4173
DOI - 10.1111/ncn3.78
Subject(s) - spinocerebellar ataxia , trinucleotide repeat expansion , indel , genetics , sequence (biology) , computational biology , intron , gene , allele , biology , medicine , genotype , single nucleotide polymorphism
Background and Aim Spinocerebellar ataxia type 10 ( SCA 10) is caused by an expansion of a normally polymorphic ATTCT repeat within intron 9 of the ATXN10 gene. Interrupting sequences in the expanded ATTCT repeat track are postulated to be a disease modifier, but are not fully characterized in SCA 10 patients. As the large size and repetitive nature of the SCA 10 expansion does not make it amenable for S anger or next‐generation sequencing, we require an alternative approach to determine whether there are interrupted repeat motifs within the SCA 10 expansion. Methods We developed a strategy that combines long‐range polymerase chain reaction and shot‐gun sequencing to characterize interruption sequences without full assembly of the entire disease allele. We chose three SCA 10‐positive individuals with disparate clinical presentations and examined the resulting sequences for interrupting motifs. Results With this strategy, we found known heptanucleotide ( ATTTTCT and ATATTCT ) and pentanucleotide ( ATCCC and ATCCT ) interruption sequences in one allele. Additionally, we found novel pentanucleotide ( ACTCT , ATTCA , ATTCC ) and heptanucleotide ( ATTCTCT ) repeat interruption motifs in two additional samples. Conclusion The present results show the utility of this approach for determining the internal repeat structure of difficult to sequence repeat expansions. Furthermore, we find that the extent and type of interrupting sequences varies dramatically between these three SCA 10‐positive individuals.