title: Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia.
abstract: Previous studies in mice have reported five different microRNAs (miRNAs; miR-219-1/132/183/96/182) to be modulators of the endogenous circadian clock and have presented experimental evidence for some of the genes involved in the molecular clock machinery as target sites. Moreover, disruption of circadian rhythms has long been implicated in the pathophysiology of major depression (MD). We investigated these miRNAs and some of their target sites at the sequence and functional levels as possible predisposing factors for susceptibility to MD and related chronobiological subphenotypes. Mutational screening was performed in a sample of 359 MD patients and 341 control individuals. We found a significant association between the T allele of the rs76481776 polymorphism in the pre-miR-182 and late insomnia in MD patients. Previous studies have reported an association between insomnia and CLOCK gene, a predicted miR-182 target site. A significant overexpression of miR-182 was detected by quantitative real-time polymerase chain reaction in cells transfected with the mutated form of the pre-miR-182 when compared with wild-type form. Moreover, a significant reduction in luciferase activity of plasmids with 3' UTR of ADCY6, CLOCK and DSIP genes was shown when transfecting cells with the mutated form of pre-miR-182 compared with cells that did not express miR-182. These data indicate that abnormal processing of pre-miR-182 in patients carrying the T allele of the rs76481776 polymorphism may contribute to the dysregulation of circadian rhythms in MD patients with insomnia, which could influence expression levels of the mature form of miR-182 and might increase downregulation in some of its target genes.
authors.affiliation: Genes and Disease Program, Center for Genomic Regulation-UPF, and CIBER en Epidemiología y Salud Pública, Barcelona 08003, Catalonia, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Saus
authors.forename: Virginia
authors.initials: V
authors.lastname: Soria
authors.forename: Geòrgia
authors.initials: G
authors.lastname: Escaramís
authors.forename: Francesca
authors.initials: F
authors.lastname: Vivarelli
authors.forename: José M
authors.initials: JM
authors.lastname: Crespo
authors.forename: Birgit
authors.initials: B
authors.lastname: Kagerbauer
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Menchón
authors.forename: Mikel
authors.initials: M
authors.lastname: Urretavizcaya
authors.forename: Mònica
authors.initials: M
authors.lastname: Gratacòs
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
mesh_terms: D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics*; D004252:DNA Mutational Analysis; D003865:Major Depressive Disorder / Q000235:genetics* / Q000503:physiopathology*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005822:Genetic Vectors; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D007319:Sleep Initiation and Maintenance Disorders / Q000235:genetics* / Q000503:physiopathology; D014162:Transfection
chemical_list: D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D012322:RNA Precursors; D056926:CLOCK Proteins; C538943:CLOCK protein, human