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Inheritance patterns of ATCCT repeat interruptions in spinocerebellar ataxia type 10 (SCA10) expansions.

Abstract Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant cerebellar ataxia disorder, is caused by a non-coding ATTCT microsatellite repeat expansion in the ataxin 10 gene. In a subset of SCA10 families, the 5'-end of the repeat expansion contains a complex sequence of penta- and heptanucleotide interruption motifs which is followed by a pure tract of tandem ATCCT repeats of unknown length at its 3'-end. Intriguingly, expansions that carry these interruption motifs correlate with an epileptic seizure phenotype and are unstable despite the theory that interruptions are expected to stabilize expanded repeats. To examine the apparent contradiction of unstable, interruption-positive SCA10 expansion alleles and to determine whether the instability originates outside of the interrupted region, we sequenced approximately 1 kb of the 5'-end of SCA10 expansions using the ATCCT-PCR product in individuals across multiple generations from four SCA10 families. We found that the greatest instability within this region occurred in paternal transmissions of the allele in stretches of pure ATTCT motifs while the intervening interrupted sequences were stable. Overall, the ATCCT interruption changes by only one to three repeat units and therefore cannot account for the instability across the length of the disease allele. We conclude that the AT-rich interruptions locally stabilize the SCA10 expansion at the 5'-end but do not completely abolish instability across the entire span of the expansion. In addition, analysis of the interruption alleles across these families support a parsimonious single origin of the mutation with a shared distant ancestor.
PMID
Related Publications

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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 28423040
OWN - NLM
STAT- In-Process
DA  - 20170419
LR  - 20170419
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Inheritance patterns of ATCCT repeat interruptions in spinocerebellar ataxia type
      10 (SCA10) expansions.
PG  - e0175958
LID - 10.1371/journal.pone.0175958 [doi]
AB  - Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant cerebellar ataxia
      disorder, is caused by a non-coding ATTCT microsatellite repeat expansion in the 
      ataxin 10 gene. In a subset of SCA10 families, the 5'-end of the repeat expansion
      contains a complex sequence of penta- and heptanucleotide interruption motifs
      which is followed by a pure tract of tandem ATCCT repeats of unknown length at
      its 3'-end. Intriguingly, expansions that carry these interruption motifs
      correlate with an epileptic seizure phenotype and are unstable despite the theory
      that interruptions are expected to stabilize expanded repeats. To examine the
      apparent contradiction of unstable, interruption-positive SCA10 expansion alleles
      and to determine whether the instability originates outside of the interrupted
      region, we sequenced approximately 1 kb of the 5'-end of SCA10 expansions using
      the ATCCT-PCR product in individuals across multiple generations from four SCA10 
      families. We found that the greatest instability within this region occurred in
      paternal transmissions of the allele in stretches of pure ATTCT motifs while the 
      intervening interrupted sequences were stable. Overall, the ATCCT interruption
      changes by only one to three repeat units and therefore cannot account for the
      instability across the length of the disease allele. We conclude that the AT-rich
      interruptions locally stabilize the SCA10 expansion at the 5'-end but do not
      completely abolish instability across the entire span of the expansion. In
      addition, analysis of the interruption alleles across these families support a
      parsimonious single origin of the mutation with a shared distant ancestor.
FAU - Landrian, Ivette
AU  - Landrian I
AD  - Department of Neurology, College of Medicine, and the McKnight Brain Institute,
      University of Florida, Gainesville, Florida, United States of America.
FAU - McFarland, Karen N
AU  - McFarland KN
AUID- ORCID: http://orcid.org/0000-0002-9952-8678
AD  - Department of Neurology, College of Medicine, and the McKnight Brain Institute,
      University of Florida, Gainesville, Florida, United States of America.
AD  - Center for Translational Research in Neurodegenerative Disease, The University of
      Florida, Gainesville, Florida, United States of America.
FAU - Liu, Jilin
AU  - Liu J
AD  - Department of Neurology, College of Medicine, and the McKnight Brain Institute,
      University of Florida, Gainesville, Florida, United States of America.
FAU - Mulligan, Connie J
AU  - Mulligan CJ
AD  - Department of Anthropology, College of Liberal Arts and Sciences, University of
      Florida, Gainesville, Florida, United States of America.
AD  - Genetics Institute, University of Florida, Gainesville, Florida, United States of
      America.
FAU - Rasmussen, Astrid
AU  - Rasmussen A
AD  - Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research
      Foundation, Oklahoma City, Oklahoma, United States of America.
FAU - Ashizawa, Tetsuo
AU  - Ashizawa T
AD  - Department of Neurology, College of Medicine, and the McKnight Brain Institute,
      University of Florida, Gainesville, Florida, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20170419
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
EDAT- 2017/04/20 06:00
MHDA- 2017/04/20 06:00
CRDT- 2017/04/20 06:00
PHST- 2016/09/14 [received]
PHST- 2017/04/03 [accepted]
AID - 10.1371/journal.pone.0175958 [doi]
AID - PONE-D-16-36937 [pii]
PST - epublish
SO  - PLoS One. 2017 Apr 19;12(4):e0175958. doi: 10.1371/journal.pone.0175958.
      eCollection 2017.

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