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Somatic instability of the expanded GAA repeats in Friedreich's ataxia.

Abstract Friedreich's ataxia (FRDA) is a genetic neurodegenerative disorder caused by transcriptional silencing of the frataxin gene (FXN) due to expansions of GAA repeats in intron 1. FRDA manifests with multiple symptoms, which may include ataxia, cardiomyopathy and diabetes mellitus. Expanded GAA tracts are genetically unstable, exhibiting both expansions and contractions. GAA length correlates with severity of FRDA symptoms and inversely with age of onset. Thus, tissue-specific somatic instability of long GAA repeats may be implicated in the development of symptoms and disease progression. Herein, we determined the extent of somatic instability of the GAA repeats in heart, cerebral cortex, spinal cord, cerebellar cortex, and pancreatic tissues from 15 FRDA patients. Results demonstrate differences in the lengths of the expanded GAAs among different tissues, with significantly longer GAA tracts detected in heart and pancreas than in other tissues. The expansion bias detected in heart and pancreas may contribute to disease onset and progression, making the mechanism of somatic instability an important target for therapy. Additionally, we detected significant differences in GAA tract lengths between lymphocytes and fibroblast pairs derived from 16 FRDA patients, with longer GAA tracts present in the lymphocytes. This result urges caution in direct comparisons of data obtained in these frequently used FRDA models. Furthermore, we conducted a longitudinal analysis of the GAA repeat length in lymphocytes collected over a span of 7-9 years and demonstrated progressive expansions of the GAAs with maximum gain of approximately 9 repeats per year. Continuous GAA expansions throughout the patient's lifespan, as observed in FRDA lymphocytes, should be considered in clinical trial designs and data interpretation.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 29261783
OWN - NLM
STAT- In-Process
LR  - 20171220
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 12
DP  - 2017
TI  - Somatic instability of the expanded GAA repeats in Friedreich's ataxia.
PG  - e0189990
LID - 10.1371/journal.pone.0189990 [doi]
AB  - Friedreich's ataxia (FRDA) is a genetic neurodegenerative disorder caused by
      transcriptional silencing of the frataxin gene (FXN) due to expansions of GAA
      repeats in intron 1. FRDA manifests with multiple symptoms, which may include
      ataxia, cardiomyopathy and diabetes mellitus. Expanded GAA tracts are genetically
      unstable, exhibiting both expansions and contractions. GAA length correlates with
      severity of FRDA symptoms and inversely with age of onset. Thus, tissue-specific 
      somatic instability of long GAA repeats may be implicated in the development of
      symptoms and disease progression. Herein, we determined the extent of somatic
      instability of the GAA repeats in heart, cerebral cortex, spinal cord, cerebellar
      cortex, and pancreatic tissues from 15 FRDA patients. Results demonstrate
      differences in the lengths of the expanded GAAs among different tissues, with
      significantly longer GAA tracts detected in heart and pancreas than in other
      tissues. The expansion bias detected in heart and pancreas may contribute to
      disease onset and progression, making the mechanism of somatic instability an
      important target for therapy. Additionally, we detected significant differences
      in GAA tract lengths between lymphocytes and fibroblast pairs derived from 16
      FRDA patients, with longer GAA tracts present in the lymphocytes. This result
      urges caution in direct comparisons of data obtained in these frequently used
      FRDA models. Furthermore, we conducted a longitudinal analysis of the GAA repeat 
      length in lymphocytes collected over a span of 7-9 years and demonstrated
      progressive expansions of the GAAs with maximum gain of approximately 9 repeats
      per year. Continuous GAA expansions throughout the patient's lifespan, as
      observed in FRDA lymphocytes, should be considered in clinical trial designs and 
      data interpretation.
FAU - Long, Ashlee
AU  - Long A
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at
      Birmingham, Birmingham, Alabama, United States of America.
FAU - Napierala, Jill S
AU  - Napierala JS
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at
      Birmingham, Birmingham, Alabama, United States of America.
FAU - Polak, Urszula
AU  - Polak U
AD  - Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, University
      of Texas MD Anderson Cancer Center, Smithville, Texas, United States of America.
FAU - Hauser, Lauren
AU  - Hauser L
AD  - Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of
      America.
FAU - Koeppen, Arnulf H
AU  - Koeppen AH
AD  - VA Medical Center, Albany, New York, United States of America.
FAU - Lynch, David R
AU  - Lynch DR
AD  - Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of
      America.
FAU - Napierala, Marek
AU  - Napierala M
AUID- ORCID: http://orcid.org/0000-0002-9987-0641
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at
      Birmingham, Birmingham, Alabama, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20171219
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
EDAT- 2017/12/21 06:00
MHDA- 2017/12/21 06:00
CRDT- 2017/12/21 06:00
PHST- 2017/09/22 00:00 [received]
PHST- 2017/12/06 00:00 [accepted]
PHST- 2017/12/21 06:00 [entrez]
PHST- 2017/12/21 06:00 [pubmed]
PHST- 2017/12/21 06:00 [medline]
AID - 10.1371/journal.pone.0189990 [doi]
AID - PONE-D-17-34504 [pii]
PST - epublish
SO  - PLoS One. 2017 Dec 19;12(12):e0189990. doi: 10.1371/journal.pone.0189990.
      eCollection 2017.