title: MicroRNA expression profiling in blood from fragile X-associated tremor/ataxia syndrome patients.
abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with FMR1 gene premutation alleles (55-200 CGG repeats). Fragile X-associated tremor/ataxia syndrome clinical core features include action tremor, gait ataxia, cognitive deficits progressing to dementia, and frequently parkinsonism. Although the pathogenic molecular mechanism of FXTAS is not completely understood, the restriction of the phenotype to the FMR1 premutation range has given rise to a model based on a RNA toxic gain-of-function. Since the identification of the first microRNAs (miRNAs) and their role in normal development, several studies have associated them with neurodegenerative diseases such as Parkinson, Alzheimer and Huntington diseases, suggesting that they play a key role in brain development, as well as in its morphogenesis. Herein, we present the characterization of miRNA expression profiles in FXTAS male patients using deep sequencing-based technologies and microarray technology. Deep sequencing analysis evidenced 83 miRNAs that were significantly deregulated whereas microarray analysis showed 31. When comparing these results, 14 miRNAs were found deregulated in FXTAS patients. MiR-424 and miR-574-3p showed significant fold change adjusted P-values in both platforms in FXTAS patients. MiR-424 has been founded substantially and specifically enriched in human cerebral cortical white matter of Alzheimer disease patients, which, together with cerebral atrophy, is a prominent imaging finding in individuals with FXTAS. The study provides the first systematic evidence of differential miRNA expression changes in FXTAS blood samples. Although further studies are necessary to better characterize the miRNA function in FXTAS disorder, our results suggest that they might contribute to its pathogenesis.
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic, Barcelona, Spain.
authors.forename: M I
authors.initials: MI
authors.lastname: Alvarez-Mora
authors.forename: L
authors.initials: L
authors.lastname: Rodriguez-Revenga
authors.forename: I
authors.initials: I
authors.lastname: Madrigal
authors.forename: F
authors.initials: F
authors.lastname: Torres-Silva
authors.forename: E
authors.initials: E
authors.lastname: Mateu-Huertas
authors.forename: E
authors.initials: E
authors.lastname: Lizano
authors.forename: M R
authors.initials: MR
authors.lastname: Friedländer
authors.forename: E
authors.initials: E
authors.lastname: Martí
authors.forename: X
authors.initials: X
authors.lastname: Estivill
authors.forename: M
authors.initials: M
authors.lastname: Milà
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002526:Cerebellar Diseases / Q000175:diagnosis / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000737:chemistry; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D035683:MicroRNAs; C497683:FMR1 protein, human; C554214:MIRN424 microrna, human; C558811:MIRN574 microRNA, human
keywords: Expression profile; FMR1 gene; FXTAS; IsomiR; high-throughput technologies; miRNAs; mitochondrial dysfunction; neurodegeneration; oxidative stress; trimming variants