Abstract
A large, non-coding ATTCT repeat expansion causes the neurodegenerative disorder, spinocerebellar ataxia type 10 (SCA10). In a subset of SCA10 patients, interruption motifs are present at the 5’ end of the expansion and strongly correlate with epileptic seizures. Thus, interruption motifs are a predictor of the epileptic phenotype and are hypothesized to act as a phenotypic modifier in SCA10. Yet, the exact internal sequence structure of SCA10 expansions remains unknown due to limitations in current technologies for sequencing across long extended tracts of tandem nucleotide repeats. We used the third generation sequencing technology, Single Molecule Real Time (SMRT) sequencing, to obtain full-length contiguous expansion sequences, ranging from 2.5 to 4.4 kb in length, from three SCA10 patients with different clinical presentations. We obtained sequence spanning the entire length of the expansion and identified the structure of known and novel interruption motifs within the SCA10 expansion. The exact interruption patterns in expanded SCA10 alleles will allow us to further investigate the potential contributions of these interrupting sequences to the pathogenic modification leading to the epilepsy phenotype in SCA10. Our results also demonstrate that SMRT sequencing is useful for deciphering long tandem repeats that pose as “gaps” in the human genome sequence.
Highlights
Spinocerebellar ataxia type 10 (SCA10) is caused by the expansion of a pentanucleotide repeat region within intron 9 of ATAXIN 10 [1]
The epilepsy phenotype in a subset of SCA10 patients highly correlates with the presence of the ATCCT-type repeat interruptions [4], which is found at the 5’ end of subject C in this paper
The typical inverse correlation between repeat length and age at onset seen in ATCCT-negative SCA10 expansions is absent in those individuals that carry these ATCCT repeat interruptions [2]
Summary
Spinocerebellar ataxia type 10 (SCA10) is caused by the expansion of a pentanucleotide repeat region within intron 9 of ATAXIN 10 [1]. This mutation belongs to a class of non-coding repeat expansions that cause other spinocerebellar ataxia disorders (SCA8, SCA12, SCA31, SCA36) as well as amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), myotonic dystrophy types 1 (DM1) and 2 (DM2), fragile X-associated tremor/ataxia syndrome. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Lucigen Corporation provided support in the form of salaries for authors RG and limited research materials, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section
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