Altered expression of the FMR1 splicing variants landscape in premutation carriers

Elizabeth Tseng, Hiu Tung Tang, Reem Rafik AlOlaby, Luke Hickey, Flora Tassone

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

FMR1 premutation carriers (55–200 CGG repeats) are at risk for developing Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder. Approximately 20% of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency (FXPOI), in addition to a number of clinical problems affecting premutation carriers throughout their life span. Marked elevation in FMR1 mRNA levels have been observed with premutation alleles resulting in RNA toxicity, the leading molecular mechanism proposed for the FMR1 associated disorders observed in premutation carriers. The FMR1 gene undergoes alternative splicing and we have recently reported that the relative abundance of all FMR1 mRNA isoforms is significantly increased in premutation carriers. In this study, we characterized the transcriptional FMR1 isoforms distribution pattern in different tissues and identified a total of 49 isoforms, some of which observed only in premutation carriers and which might play a role in the pathogenesis of FXTAS. Further, we investigated the distribution pattern and expression levels of the FMR1 isoforms in asymptomatic premutation carriers and in those with FXTAS and found no significant differences between the two groups. Our findings suggest that the characterization of the expression levels of the different FMR1 isoforms is fundamental for understanding the regulation of the FMR1 gene as imbalance in their expression could lead to an altered functional diversity with neurotoxic consequences. Their characterization will also help to elucidating the mechanism(s) by which “toxic gain of function” of the FMR1 mRNA may play a role in FXTAS and/or in the other FMR1-associated conditions.

Original languageEnglish (US)
Pages (from-to)1117-1126
Number of pages10
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1860
Issue number11
DOIs
StatePublished - Nov 1 2017

Fingerprint

Protein Isoforms
Genes
Primary Ovarian Insufficiency
RNA Isoforms
Messenger RNA
Poisons
Alternative Splicing
Neurodegenerative Diseases
Toxicity
Alleles
RNA
Tissue
Fragile X Tremor Ataxia Syndrome

Keywords

  • Alternative splicing
  • FMR1 gene
  • FXTAS
  • Isoforms
  • RNA toxicity
  • SMRT sequencing

ASJC Scopus subject areas

  • Structural Biology
  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Altered expression of the FMR1 splicing variants landscape in premutation carriers. / Tseng, Elizabeth; Tang, Hiu Tung; AlOlaby, Reem Rafik; Hickey, Luke; Tassone, Flora.

In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, Vol. 1860, No. 11, 01.11.2017, p. 1117-1126.

Research output: Contribution to journalArticle

Tseng, Elizabeth ; Tang, Hiu Tung ; AlOlaby, Reem Rafik ; Hickey, Luke ; Tassone, Flora. / Altered expression of the FMR1 splicing variants landscape in premutation carriers. In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms. 2017 ; Vol. 1860, No. 11. pp. 1117-1126.
@article{85cf4ca714cb496abd6fcd889a786f67,
title = "Altered expression of the FMR1 splicing variants landscape in premutation carriers",
abstract = "FMR1 premutation carriers (55–200 CGG repeats) are at risk for developing Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder. Approximately 20{\%} of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency (FXPOI), in addition to a number of clinical problems affecting premutation carriers throughout their life span. Marked elevation in FMR1 mRNA levels have been observed with premutation alleles resulting in RNA toxicity, the leading molecular mechanism proposed for the FMR1 associated disorders observed in premutation carriers. The FMR1 gene undergoes alternative splicing and we have recently reported that the relative abundance of all FMR1 mRNA isoforms is significantly increased in premutation carriers. In this study, we characterized the transcriptional FMR1 isoforms distribution pattern in different tissues and identified a total of 49 isoforms, some of which observed only in premutation carriers and which might play a role in the pathogenesis of FXTAS. Further, we investigated the distribution pattern and expression levels of the FMR1 isoforms in asymptomatic premutation carriers and in those with FXTAS and found no significant differences between the two groups. Our findings suggest that the characterization of the expression levels of the different FMR1 isoforms is fundamental for understanding the regulation of the FMR1 gene as imbalance in their expression could lead to an altered functional diversity with neurotoxic consequences. Their characterization will also help to elucidating the mechanism(s) by which “toxic gain of function” of the FMR1 mRNA may play a role in FXTAS and/or in the other FMR1-associated conditions.",
keywords = "Alternative splicing, FMR1 gene, FXTAS, Isoforms, RNA toxicity, SMRT sequencing",
author = "Elizabeth Tseng and Tang, {Hiu Tung} and AlOlaby, {Reem Rafik} and Luke Hickey and Flora Tassone",
year = "2017",
month = "11",
day = "1",
doi = "10.1016/j.bbagrm.2017.08.007",
language = "English (US)",
volume = "1860",
pages = "1117--1126",
journal = "Biochimica et Biophysica Acta - Gene Regulatory Mechanisms",
issn = "1874-9399",
publisher = "Elsevier",
number = "11",

}

TY - JOUR

T1 - Altered expression of the FMR1 splicing variants landscape in premutation carriers

AU - Tseng, Elizabeth

AU - Tang, Hiu Tung

AU - AlOlaby, Reem Rafik

AU - Hickey, Luke

AU - Tassone, Flora

PY - 2017/11/1

Y1 - 2017/11/1

N2 - FMR1 premutation carriers (55–200 CGG repeats) are at risk for developing Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder. Approximately 20% of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency (FXPOI), in addition to a number of clinical problems affecting premutation carriers throughout their life span. Marked elevation in FMR1 mRNA levels have been observed with premutation alleles resulting in RNA toxicity, the leading molecular mechanism proposed for the FMR1 associated disorders observed in premutation carriers. The FMR1 gene undergoes alternative splicing and we have recently reported that the relative abundance of all FMR1 mRNA isoforms is significantly increased in premutation carriers. In this study, we characterized the transcriptional FMR1 isoforms distribution pattern in different tissues and identified a total of 49 isoforms, some of which observed only in premutation carriers and which might play a role in the pathogenesis of FXTAS. Further, we investigated the distribution pattern and expression levels of the FMR1 isoforms in asymptomatic premutation carriers and in those with FXTAS and found no significant differences between the two groups. Our findings suggest that the characterization of the expression levels of the different FMR1 isoforms is fundamental for understanding the regulation of the FMR1 gene as imbalance in their expression could lead to an altered functional diversity with neurotoxic consequences. Their characterization will also help to elucidating the mechanism(s) by which “toxic gain of function” of the FMR1 mRNA may play a role in FXTAS and/or in the other FMR1-associated conditions.

AB - FMR1 premutation carriers (55–200 CGG repeats) are at risk for developing Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder. Approximately 20% of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency (FXPOI), in addition to a number of clinical problems affecting premutation carriers throughout their life span. Marked elevation in FMR1 mRNA levels have been observed with premutation alleles resulting in RNA toxicity, the leading molecular mechanism proposed for the FMR1 associated disorders observed in premutation carriers. The FMR1 gene undergoes alternative splicing and we have recently reported that the relative abundance of all FMR1 mRNA isoforms is significantly increased in premutation carriers. In this study, we characterized the transcriptional FMR1 isoforms distribution pattern in different tissues and identified a total of 49 isoforms, some of which observed only in premutation carriers and which might play a role in the pathogenesis of FXTAS. Further, we investigated the distribution pattern and expression levels of the FMR1 isoforms in asymptomatic premutation carriers and in those with FXTAS and found no significant differences between the two groups. Our findings suggest that the characterization of the expression levels of the different FMR1 isoforms is fundamental for understanding the regulation of the FMR1 gene as imbalance in their expression could lead to an altered functional diversity with neurotoxic consequences. Their characterization will also help to elucidating the mechanism(s) by which “toxic gain of function” of the FMR1 mRNA may play a role in FXTAS and/or in the other FMR1-associated conditions.

KW - Alternative splicing

KW - FMR1 gene

KW - FXTAS

KW - Isoforms

KW - RNA toxicity

KW - SMRT sequencing

UR - http://www.scopus.com/inward/record.url?scp=85030122677&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030122677&partnerID=8YFLogxK

U2 - 10.1016/j.bbagrm.2017.08.007

DO - 10.1016/j.bbagrm.2017.08.007

M3 - Article

C2 - 28888471

AN - SCOPUS:85030122677

VL - 1860

SP - 1117

EP - 1126

JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms

JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms

SN - 1874-9399

IS - 11

ER -