Abstract
BackgroundSchizophrenia is a severe disabling brain disease affecting about 1% of the population. Individual microRNAs (miRNAs) affect moderate downregulation of gene expression. In addition, components required for miRNA processing and/or function have also been implicated in X-linked mental retardation, neurological and neoplastic diseases, pointing to the wide ranging involvement of miRNAs in disease.Methods and FindingsTo explore the role of miRNAs in schizophrenia, 59 microRNA genes on the X-chromosome were amplified and sequenced in males with (193) and without (191) schizophrenia spectrum disorders to test the hypothesis that ultra-rare mutations in microRNA collectively contribute to the risk of schizophrenia. Here we provide the first association of microRNA gene dysfunction with schizophrenia. Eight ultra-rare variants in the precursor or mature miRNA were identified in eight distinct miRNA genes in 4% of analyzed males with schizophrenia. One ultra-rare variant was identified in a control sample (with a history of depression) (8/193 versus 1/191, p = 0.02 by one-sided Fisher's exact test, odds ratio = 8.2). These variants were not found in an additional 7,197 control X-chromosomes.ConclusionsFunctional analyses of ectopically expressed copies of the variant miRNA precursors demonstrate loss of function, gain of function or altered expression levels. While confirmation is required, this study suggests that microRNA mutations can contribute to schizophrenia.
Highlights
Schizophrenia typically presents in early adulthood or late adolescence
This study suggests that microRNA mutations can contribute to schizophrenia
For most miRNA/target combinations, a single nucleotide change in the seed sequence or a mutation in the miRNA or precursor affecting the Drosha/DGCR8 or Dicer/TRBP processing step can result in altered function or creation of a novel miRNA [6,7,8,9]
Summary
Schizophrenia typically presents in early adulthood or late adolescence. Men have an earlier age of onset than women, and tend to experience a more serious form of the illness with more negative symptoms, poorer chances of a full recovery, and a generally worse outcome [1]. MiRNAs bind to complementary sites in target mRNAs, generally at 39 untranslated regions (UTRs), to create imperfectly paired miRNA/mRNA heteroduplexes that inhibit translation or increase degradation of target mRNAs. MiRNA genes are scattered among all the chromosomes in humans, except for the Y- chromosome. The pri-miRNAs are processed to hairpin like structures termed precursor miRNA (pre-miRNA). Translational suppression and mRNA degradation, modes by which mammalian miRNAs regulate gene expression, do not require complete complementarity between the miRNA and target. For the majority of miRNA/target combinations, the seed sequence complementarity is a pre-requisite, there are some exceptions which complicate target site predictions. For most miRNA/target combinations, a single nucleotide change in the seed sequence or a mutation in the miRNA or precursor affecting the Drosha/DGCR8 or Dicer/TRBP processing step can result in altered function or creation of a novel miRNA [6,7,8,9]. Components required for miRNA processing and/ or function have been implicated in X-linked mental retardation, neurological and neoplastic diseases, pointing to the wide ranging involvement of miRNAs in disease
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