Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability

Karen N. McFarland, Jilin Liu, Ivette Landrian, Rui Gao, Partha Sarkar, Salmo Raskin, Mariana Moscovich, Emilia M. Gatto, Hélio A G Teive, Adriana Ochoa, Astrid Rasmussen, Tetsuo Ashizawa

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder caused by a noncoding ATTCT pentanucleotide expansion. An inverse correlation between SCA10 expansion size and age at onset has been reported, and genetic anticipation has been documented. Interruptions in the ATTCT expansion are known to occur within the expansion. In order to determine the effect of repeat interruptions in SCA10 expansions, we designed a PCR assay to easily identify ATCCT repeat interruptions in the 5′-end of the expansion. We screened a cohort of 31 SCA10 families of Mexican, Brazilian and Argentinean ancestry to identify those with ATCCT repeat interruptions within their SCA10 expansions. We then studied the effects of ATCCT interruptions on intergenerational repeat instability, anticipation and age at onset. We find that the SCA10 expansion size is larger in SCA10 patients with an interrupted allele, but there is no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles show anticipation but are accompanied by a paradoxical contraction in intergenerational repeat size. In conclusion, we find that SCA10 expansions with ATCCT interruptions dramatically differ from SCA10 expansions without detectable ATCCT interruptions in repeat-size-instability dynamics and pathogenicity.

Original languageEnglish (US)
Pages (from-to)1272-1276
Number of pages5
JournalEuropean Journal of Human Genetics
Volume21
Issue number11
DOIs
StatePublished - Nov 2013

Fingerprint

Age of Onset
Alleles
Genetic Anticipation
Spinocerebellar Ataxia 10
Neurodegenerative Diseases
Virulence
Polymerase Chain Reaction

Keywords

  • anticipation
  • repeat instability
  • repeat interruptions

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability. / McFarland, Karen N.; Liu, Jilin; Landrian, Ivette; Gao, Rui; Sarkar, Partha; Raskin, Salmo; Moscovich, Mariana; Gatto, Emilia M.; Teive, Hélio A G; Ochoa, Adriana; Rasmussen, Astrid; Ashizawa, Tetsuo.

In: European Journal of Human Genetics, Vol. 21, No. 11, 11.2013, p. 1272-1276.

Research output: Contribution to journalArticle

McFarland, KN, Liu, J, Landrian, I, Gao, R, Sarkar, P, Raskin, S, Moscovich, M, Gatto, EM, Teive, HAG, Ochoa, A, Rasmussen, A & Ashizawa, T 2013, 'Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability', European Journal of Human Genetics, vol. 21, no. 11, pp. 1272-1276. https://doi.org/10.1038/ejhg.2013.32
McFarland, Karen N. ; Liu, Jilin ; Landrian, Ivette ; Gao, Rui ; Sarkar, Partha ; Raskin, Salmo ; Moscovich, Mariana ; Gatto, Emilia M. ; Teive, Hélio A G ; Ochoa, Adriana ; Rasmussen, Astrid ; Ashizawa, Tetsuo. / Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability. In: European Journal of Human Genetics. 2013 ; Vol. 21, No. 11. pp. 1272-1276.
@article{d67d0a27a860477ea35005bf7739defe,
title = "Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability",
abstract = "Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder caused by a noncoding ATTCT pentanucleotide expansion. An inverse correlation between SCA10 expansion size and age at onset has been reported, and genetic anticipation has been documented. Interruptions in the ATTCT expansion are known to occur within the expansion. In order to determine the effect of repeat interruptions in SCA10 expansions, we designed a PCR assay to easily identify ATCCT repeat interruptions in the 5′-end of the expansion. We screened a cohort of 31 SCA10 families of Mexican, Brazilian and Argentinean ancestry to identify those with ATCCT repeat interruptions within their SCA10 expansions. We then studied the effects of ATCCT interruptions on intergenerational repeat instability, anticipation and age at onset. We find that the SCA10 expansion size is larger in SCA10 patients with an interrupted allele, but there is no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles show anticipation but are accompanied by a paradoxical contraction in intergenerational repeat size. In conclusion, we find that SCA10 expansions with ATCCT interruptions dramatically differ from SCA10 expansions without detectable ATCCT interruptions in repeat-size-instability dynamics and pathogenicity.",
keywords = "anticipation, repeat instability, repeat interruptions",
author = "McFarland, {Karen N.} and Jilin Liu and Ivette Landrian and Rui Gao and Partha Sarkar and Salmo Raskin and Mariana Moscovich and Gatto, {Emilia M.} and Teive, {H{\'e}lio A G} and Adriana Ochoa and Astrid Rasmussen and Tetsuo Ashizawa",
year = "2013",
month = "11",
doi = "10.1038/ejhg.2013.32",
language = "English (US)",
volume = "21",
pages = "1272--1276",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability

AU - McFarland, Karen N.

AU - Liu, Jilin

AU - Landrian, Ivette

AU - Gao, Rui

AU - Sarkar, Partha

AU - Raskin, Salmo

AU - Moscovich, Mariana

AU - Gatto, Emilia M.

AU - Teive, Hélio A G

AU - Ochoa, Adriana

AU - Rasmussen, Astrid

AU - Ashizawa, Tetsuo

PY - 2013/11

Y1 - 2013/11

N2 - Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder caused by a noncoding ATTCT pentanucleotide expansion. An inverse correlation between SCA10 expansion size and age at onset has been reported, and genetic anticipation has been documented. Interruptions in the ATTCT expansion are known to occur within the expansion. In order to determine the effect of repeat interruptions in SCA10 expansions, we designed a PCR assay to easily identify ATCCT repeat interruptions in the 5′-end of the expansion. We screened a cohort of 31 SCA10 families of Mexican, Brazilian and Argentinean ancestry to identify those with ATCCT repeat interruptions within their SCA10 expansions. We then studied the effects of ATCCT interruptions on intergenerational repeat instability, anticipation and age at onset. We find that the SCA10 expansion size is larger in SCA10 patients with an interrupted allele, but there is no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles show anticipation but are accompanied by a paradoxical contraction in intergenerational repeat size. In conclusion, we find that SCA10 expansions with ATCCT interruptions dramatically differ from SCA10 expansions without detectable ATCCT interruptions in repeat-size-instability dynamics and pathogenicity.

AB - Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder caused by a noncoding ATTCT pentanucleotide expansion. An inverse correlation between SCA10 expansion size and age at onset has been reported, and genetic anticipation has been documented. Interruptions in the ATTCT expansion are known to occur within the expansion. In order to determine the effect of repeat interruptions in SCA10 expansions, we designed a PCR assay to easily identify ATCCT repeat interruptions in the 5′-end of the expansion. We screened a cohort of 31 SCA10 families of Mexican, Brazilian and Argentinean ancestry to identify those with ATCCT repeat interruptions within their SCA10 expansions. We then studied the effects of ATCCT interruptions on intergenerational repeat instability, anticipation and age at onset. We find that the SCA10 expansion size is larger in SCA10 patients with an interrupted allele, but there is no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles show anticipation but are accompanied by a paradoxical contraction in intergenerational repeat size. In conclusion, we find that SCA10 expansions with ATCCT interruptions dramatically differ from SCA10 expansions without detectable ATCCT interruptions in repeat-size-instability dynamics and pathogenicity.

KW - anticipation

KW - repeat instability

KW - repeat interruptions

UR - http://www.scopus.com/inward/record.url?scp=84885901259&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885901259&partnerID=8YFLogxK

U2 - 10.1038/ejhg.2013.32

DO - 10.1038/ejhg.2013.32

M3 - Article

C2 - 23443018

AN - SCOPUS:84885901259

VL - 21

SP - 1272

EP - 1276

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 11

ER -