Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes

Elisabet Mateu-Huertas, Laia Rodriguez-Revenga, Maria Isabel Alvarez-Mora, Irene Madrigal, Rob Willemsen, Montserrat Milà, Eulàlia Martí, Xavier P. Estivill

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5'-UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.

Original languageEnglish
Pages (from-to)43-54
Number of pages12
JournalNeurobiology of Disease
Volume65
DOIs
Publication statusPublished - May 2014
Externally publishedYes

Fingerprint

Infertility
Phenotype
Transcriptome
Genes
Gene Expression Profiling
Primary Ovarian Insufficiency
Messenger RNA
5' Untranslated Regions
Fragile X Tremor Ataxia Syndrome
Homeostasis
Down-Regulation
Inflammation
Brain

Keywords

  • Early at menopause 1 (EAP1)
  • Fragile X associated Premature Ovarian Insufficiency
  • Fragile X Tremor/Ataxia Syndrome
  • Histone deacetylase 5 (HDAC5)

ASJC Scopus subject areas

  • Neurology

Cite this

Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes. / Mateu-Huertas, Elisabet; Rodriguez-Revenga, Laia; Alvarez-Mora, Maria Isabel; Madrigal, Irene; Willemsen, Rob; Milà, Montserrat; Martí, Eulàlia; Estivill, Xavier P.

In: Neurobiology of Disease, Vol. 65, 05.2014, p. 43-54.

Research output: Contribution to journalArticle

Mateu-Huertas, Elisabet ; Rodriguez-Revenga, Laia ; Alvarez-Mora, Maria Isabel ; Madrigal, Irene ; Willemsen, Rob ; Milà, Montserrat ; Martí, Eulàlia ; Estivill, Xavier P. / Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes. In: Neurobiology of Disease. 2014 ; Vol. 65. pp. 43-54.
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AU - Madrigal, Irene

AU - Willemsen, Rob

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AU - Martí, Eulàlia

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